A Review of Current Guidelines for Depression Treatment

Alan J. Gelenberg, MD

Department of Psychiatry, Penn State College of Medicine, Hershey, Pennsylvania

Major Treatment Guidelines Since 2000

The last full update to the APA treatment guideline for depression was in 2000,1 which was followed by a partial update in 2005.2 The APA is in the process of preparing a full update, but, as of this publication, new guidelines have not yet been released. Since 2000, other major Western guidelines for the treatment of depression include those released by the WFSBP in 20023,4 and 2007,5 the BAP6 and the TMAP in 2008,7 and the NICE8 and the CANMAT in 20099 (AV 1AV 1). For a more detailed review of these guidelines, see the supplement article “Major Depressive Disorder Treatment Guidelines in America and Europe” by Jonathan R.T. Davidson, MD.

Each of these guidelines addresses both major depression and subthreshold or mild depression with the exception of the CANMAT and TMAP guidelines, which cover only MDD. Psychiatrists are the intended audience for all of the guidelines except the 2007 edition of the WFSBP guidelines, which is for physicians in primary care. The NICE and BAP guidelines address both psychiatrists and primary care providers.

Consensus Among Guidelines

All major guidelines for the treatment of depression agree upon the need for a biopsychosocial assessment of stressors, patients’ overall health issues, and any risk of harm that patients may pose to themselves or to others (AV 2AV 2).10 Other universal recommendations include individualizing treatment according to patients’ profiles and needs, using standardized measurement tools to track symptomatology, prescribing an appropriate dosage of a medication for an adequate duration, and treating patients to remission—that is, suppressing virtually all depressive symptoms.

Although all major international guidelines for the treatment of depression are evidence-based, treatment recommendations may occasionally be influenced by factors such as the composition of the author group or an underlying mandate, political or otherwise. Cultural perceptions of mental illness vary and can influence treatment recommendations. For example, certain cultures might view medication as less necessary for anxiety than for depression. However, the American and European guidelines tend to agree on the basic principles of treatment for major depression, especially moderate and severe cases.

First-Line Treatments for Depression by Severity

Mild depression. Depending on the guideline, treatment recommendations for mild depression range from antidepressant pharmacotherapy or psychotherapy (or the combination) to exercise and CAM treatments to active monitoring if a possibility exists that the episode might resolve itself. The NICE guideline for mild depression also includes the options of computer-delivered CBT and guided self-help as well as sleep hygiene education. The general idea is that low-intensity treatments should be tried first, depending on the patient’s history; if the patient has chronic depression or has previously had a severe episode, then antidepressant or evidence-based psychotherapies are appropriate first-line treatments for mild depression.

Moderate depression. Generally, first-line treatment recommendations for moderate depression are antidepressant monotherapy, some form of psychotherapy as monotherapy, or a combination of the 2, especially when the patient has significant psychosocial problems or a comorbid Axis II disorder. Commonly recommended first-line pharmacotherapeutic options include SSRIs, SNRIs, bupropion, and mirtazapine. Recommended psychotherapeutic methods include CBT, IPT, cognitive therapy, and behavior therapy with activity scheduling.

Severe depression. For severe depression, probably the most elaborate guideline comes from TMAP, which offers a 6-stage algorithm for psychotic major depression along with its algorithm for nonpsychotic MDD.7 In all of the guidelines, first-line treatment options are ECT, a combination of an antidepressant and psychotherapy, or, if the patient has psychotic features, a combination of antidepressant and antipsychotic medications.

Tracking response and remission. The definitions of response and remission vary from guideline to guideline. The TMAP guideline uses specific QIDS-1611 score ranges to define response and remission, whereas percentage of change in symptomatology is used by the WFSBP and CANMAT guidelines. The APA, BAP, and NICE guidelines are less specific but recommend employing measurement-based care.

Most guidelines agree that first-line treatments need a trial of 8 to 12 weeks. Upon initiation of treatment, clinicians should schedule patient visits every 1 or 2 weeks to assess improvement (or the lack of improvement) and doses should be gradually and persistently increased until either remission is achieved or patients’ tolerance limits are reached. At least 4 weeks of treatment at an adequate dose are needed before response can be determined.

Second-Line Treatment Strategies

If remission has not occurred after adequate first-line treatment, second-line treatment is needed. In some guidelines, short-term continuation of the first-line medication, with or without an increase in dosage, is recommended as a second-line option if partial response has occurred with no intolerable side effects. Another option for partial response is augmentation with a second antidepressant that has a different mechanism of action. If response to the first-line treatment was poor—eg, < 20% to 25% improvement—then switching to a different antidepressant or to psychotherapy is recommended.

Despite the guideline recommendations, neither switching nor augmentation were found to be particularly effective second-line strategies in STAR*D (AV 3AV 3).12 The overall remission rate in STAR*D for second-step subjects—a group comprising approximately 63% of total study subjects—was about 30%. In fact, the likelihood of response or remission decreased with each additional treatment stage. Therefore, choosing the first-line treatment option that best suits a patient’s individual illness profile is crucial.


Continuation and Maintenance Treatment

Major treatment guidelines for depression agree that patients who reach remission should continue their treatment at the same dosage for at least 6 to 9 months to achieve recovery (AV 2AV 2). Maintenance treatment is usually needed beyond 1 year. Because episodes of major depression are associated with high rates of recurrence, many patients will require long-term or even lifetime treatment. During the continuation or maintenance phases, clinicians should meet with patients regularly and pay particular attention to treatment adherence. If antidepressant pharmacotherapy is withdrawn, discontinuation should be gradual, although the specifics of discontinuation may vary among different medications.

APA Treatment Guidelines for MDD, 3rd Edition

The revised edition of the APA treatment guideline for MDD is expected to be published in early 2010. New developments since the 2000 edition that will be addressed in the new edition include issues surrounding antidepressants and suicidality; major clinical trials such as STAR*D,13 REVAMP,14 and PREVENT15; ECT; CAM treatments; and new research concerning psychotherapy and antidepressant pharmacotherapy.

Several new agents from different drug classes have been studied and used for the treatment of depression since the last APA guidelines were published.1,2 Some of the new drugs are achieving better results than others, but none of the new options dramatically improve the current state of antidepressant therapy. Of note, some atypical antipsychotics have been found to be useful as adjuncts, and perhaps even as monotherapy, in MDD.

Cipriani and colleagues16 conducted a meta-analysis evaluating 12 of the new antidepressants for efficacy, tolerability, and overall value. The agents mirtazapine, escitalopram, venlafaxine, and sertraline were reported to be more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine (AV 4AV 4).17 When considering all-cause discontinuation, the authors found that escitalopram and sertraline had the best tolerability profiles. Sertraline, which is available as a generic drug, appears to be the most cost-effective option overall and stands out as a potential first-line recommendation for the new APA guideline.

Advances have been made in the realm of nonpharmacologic treatments for depression, although, as with medication, none is a clear breakthrough. Psychotherapeutic techniques such as CBT and IPT have demonstrated efficacy in the acute and maintenance treatment phases for depression, both as monotherapy and in combination with pharmacotherapy.17


Evidence-based treatment guidelines are necessary and generally make the same recommendations concerning the treatment of depression. SSRIs, SNRIs, bupropion, and evidence-based psychotherapy are the main first-line treatments endorsed by current guidelines. Treatments should be individualized according to patient profiles. Selection of a drug or psychotherapy takes place within the context of treatment acceptability to patients and their families because the only treatment that works is the treatment that patients actually adhere to.

Measurement-based care is essential in strategically deciding when to continue a particular treatment or to move on to another therapy. Of the accepted treatment strategies for depression, no single approach is always better than another, which was demonstrated dramatically by the STAR*D study.13 Some strategies may have more evidence of efficacy than others, but multiple factors affect study outcomes, including depressive severity and subtype, number and length of previous episodes, type and duration of previous treatment, comorbidities, and other population specifics. As such, personalized medicine using genetic testing for patients with MDD remains an ideal for which to strive.

For Clinical Use

  • Consult evidence-based guidelines for all steps of the depression treatment process from diagnosis to maintenance therapy
  • Individualize treatment selection as much as possible
  • Use measurement-based care and standardized measurement tools when assessing patient progress

Drug Names

bupropion (Aplenzin, Wellbutrin, and others), duloxetine (Cymbalta), escitalopram (Lexapro and others), fluoxetine (Prozac and others), fluvoxamine (Luvox and others), mirtazapine (Remeron and others), paroxetine (Paxil, Pexeva, and others), sertraline (Zoloft and others), venlafaxine (Effexor and others)


APA=American Psychiatric Association, BAP=British Association of Psychopharmacology, CAM=complementary and alternative medicine, CBT=cognitive-behavioral therapy, CANMAT=Canadian Network for Mood and Anxiety Treatments, ECT=electroconvulsive therapy, IPT=interpersonal therapy, MDD=major depressive disorder, NICE=National Institute for Health and Clinical Excellence, PREVENT=Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years, QIDS-16=16-Item Quick Inventory of Depressive Symptomatology, REVAMP=Research Evaluating the Value of Augmenting Medication With Psychotherapy, SNRI=serotonin-norepinephrine reuptake inhibitor, SSRI=selective serotonin reuptake inhibitor, STAR*D=Sequenced Treatment Alternatives to Relieve Depression, TMAP=Texas Medication Algorithm Project, WFSBP=World Federation of Societies of Biological Psychiatry

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