Treatin​g Depression in Primary Care: Initial and Follow-Up Treatment Strategies

J. Sloan Manning, MD

Department of Family Medicine, University of North Carolina, Chapel Hill, and the Mood Disorders Clinic, Moses Cone Family Practice Center, Greensboro

W. Clay Jackson, MD, DipTh

Departments of Family Medicine and Psychiatry, University of Tennessee College of Medicine, Memphis

Because patients often require diagnosis and treatment of depression from their PCP rather than from a psychiatrist, PCPs must be prepared with treatment strategies to help their patients achieve remission, or an end to the depressive episode. While response (substantial symptomatic improvement) is the initial goal of treatment, robust, sustained remission is the ultimate goal because it is associated with a return to better functioning and reduced risk of relapse.1 As the STAR*D study1 showed, PCPs can successfully treat depression by following a rational plan that includes adequate doses of antidepressant medication, careful monitoring of symptoms and side effects, and timely treatment adjustments when necessary.

Initial Treatment Strategies

For patients diagnosed with a major depressive episode, APA guidelines2 recommend treatment with antidepressant medication, psychotherapy, or device therapies (such as ECT) as well as education about healthy behaviors such as exercise. PCPs should base treatment decisions on the patient’s severity of symptoms, comorbid conditions, preference, and prior treatment experiences.2

Pharmacotherapy. Antidepressant medication is recommended as a first-line treatment strategy for patients with mild to severe MDD.2 Commonly used antidepressants include SSRIs (such as fluoxetine, citalopram, escitalopram, sertraline, paroxetine), SNRIs (like venlafaxine and duloxetine), the norepinephrine-serotonin modulator mirtazapine, and the norepinephrine and dopamine reuptake inhibitor bupropion. Vortioxetine, an antidepressant with SSRI activity plus modulatory effects on other serotonergic receptors, has also recently become available. Less commonly used options include TCAs (eg, amitriptyline), MAOIs (phenelzine, tranylcypromine), and 5-HT2 antagonists (trazodone, nefazodone). Depending on their mechanism of action, antidepressants are associated with different safety profiles and adverse effects. For example, MAOIs require dietary restrictions and have potentially serious side effects and drug interactions, which limit their use, while SSRIs are associated with less serious side effects, such as gastrointestinal problems, sleep disturbances, and sexual dysfunction.2

Because antidepressants are thought to have comparable efficacy, medication choice may be determined by other factors including half-life, cost, patient preference, and anticipated side effects.2 A meta-analysis3 of 12 antidepressants revealed that escitalopram, sertraline, citalopram, and bupropion were better tolerated than other antidepressants (based on fewer treatment discontinuations), while mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. Vortioxetine is also well tolerated across its approved dosing range, with discontinuation from adverse effects in pooled analyses ranging from 5% to 8% compared with 4% for placebo.4 However, PCPs must determine which agent will be the best balance of efficacy and tolerability based on an individual patient’s co-occurring conditions, preferences, and history.

Psychotherapy. Psychotherapy is a viable treatment option for patients with mild-to-moderate MDD.2 Several types of psychotherapy (CBT, IPT) have demonstrated efficacy in treating depression and, compared with medication, may also reduce the risk of relapse after treatment is completed.2,5 For example, in a study6 comparing behavioral activation, cognitive therapy, and antidepressants in adults with major depression, the patients who continued to receive medication or had prior behavioral activation or cognitive therapy had fewer relapses through 1-year follow-up compared with patients whose medication had been switched to placebo.

Another study7 found that among unstable remitters who were assigned to either continued antidepressant medication or to 8 weeks of MBCT, a group-based psychosocial intervention, patients in both groups showed a 73% decrease in relapse risk compared with those assigned to placebo after antidepressant discontinuation. For patients who cannot tolerate or take antidepressants (for example, women who want to become pregnant) or who prefer alternate forms of therapy, psychotherapy may be an appropriate treatment option.2 Other factors that suggest psychotherapy as a first-choice treatment include depression closely tied to psychosocial stressors (eg, bereavement, life change), prior psychotherapy response, and treatment availability. With the development of mobile apps for conducting MBCT and CBT (eg, Thought Diary, Mood and Anxiety Diary, Activity Diary), more patients may be able to take advantage of the applications of some principles of these therapies even if they do not have access to a trained specialist.

A significant advantage of psychotherapy is its emphasis on enhancing functional recovery (the presence of wellness).8 For example, the focus of well-being therapy is to improve 6 dimensions of well-being through cognitive-behavioral techniques (AV 1).8,9 This therapy can be used for relapse prevention, for adjunctive treatment with other CBT, or for patients with suboptimal response to antidepressants or other psychotherapy.9

AV 1. Six Dimensions of Well-Being (00:31)

Based on Ryff and Singer8

Another strategy for treating depression is to increase positive emotion, engagement, and meaning rather than to target depressive symptoms directly. This positive psychotherapy approach, delivered to either individuals or groups via live interaction or through web exercises, has decreased depression and improved remission rates over those of treatment as usual.10

Device therapies. Several device therapies have been successful, in varying degrees, for treating depression using stimulation with electricity, magnets, or implants.11 As the best-studied stimulation therapy, ECT is recommended for patients with severe MDD that is unresponsive to other treatments, for patients who are psychotic or catatonic, or for individuals with significant risk of self-harm (such as those at high risk for suicide or with severe eating disorders).2 Newer, more experimental therapies include transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation. While these newer therapies show promise for treating severe or refractory depression, their safety profiles require more research.11


Exercise. Some patients may prefer to try exercise as an initial treatment, but they must be monitored for worsening mood or physical problems.2 Although few robust trials comparing exercise with other interventions exist, a meta-analysis12 found that exercise showed moderate efficacy for reducing depressive symptoms. A randomized, controlled trial13 found that patients either taking medication or exercising (at home or in a supervised group setting) had higher remission rates than those taking placebo (AV 2). This study showed that exercise in patients with MDD was comparable to antidepressant treatment.

AV 2. MDD Remission With Exercise Versus Pharmacotherapy (N=202) (00:32)

Data from Blumenthal et al13
Remission = no longer meeting criteria for MDD and having an HDRS score <8

Both aerobic and resistance exercise, alone or in combination, have efficacy for treating a range of depression severity across age groups.14 Exercise type should be determined by patient preference, access to resources, and social support.14 A meta-analysis15 of the effects of exercise on depression found a significant difference in effect sizes for exercising 5 times a week (–3.52) versus 2 to 4 times (–1.05 and –1.06, respectively; P<.01). Some patients may be interested in tracking food and exercise using smartphone apps, such as My Fitness Pal.

Exercise may also be used as an augmentation treatment with antidepressants or psychotherapy for patients with depression of any severity.2 In a study16 of patients (N=126) with nonremitted MDD who augmented SSRI treatment with high-dose and low-dose exercise, the high-dose exercise group experienced a 28% remission rate at 12 weeks, compared with 16% for the low-dose exercise group (P<.06). The best exercise regimen is one that patients will enjoy and maintain.

Follow-Up Treatment Strategies

After treatment is begun, PCPs must monitor patients’ response and identify troublesome side effects, especially those that may cause nonadherence. (For more information about monitoring strategies, see “Providing Guideline-Concordant Assessment and Monitoring for Major Depression in Primary Care.” Clinicians should track depressive symptoms using a rating scale (eg, PHQ-9, HDRS, QIDS-SR) as well as measure functional status (eg, SDS). It may also be helpful to track patients’ sense of wellness using a tool such as the WHO-5.

For most patients, the path to remission requires several drug trials using adequate doses for a sufficient duration, which typically means maximum tolerable doses for up to 8 weeks.1 APA guidelines recommend assessing treatment response every 4 to 8 weeks.2 However, a lack of improvement during the first 2 weeks of treatment may predict nonresponse, indicating that clinicians may consider an early treatment change.17

For patients with poor response after 2 adequate treatment trials, clinicians should reassess adherence, review the diagnosis, and recheck patients for medical conditions and mental disorders, including alcohol and substance use disorders.2 Because the likelihood of remission decreases precipitously after 2 medication trials,1 clinicians should carefully consider strategies if the first treatment fails. These strategies include switching or adding antidepressants or psychotherapy, changing the psychotherapy type or intensity, adjunctive therapy with atypical antipsychotics or other non-antidepressants, or using ECT.2

Switching agents. Switching antidepressants, especially among newer agents such as SSRIs, bupropion, mirtazapine, and venlafaxine, is a well-supported strategy (AV 3).18 Depending on whether patients show partial or no response to current therapy, clinicians may choose to switch agents within the same class (SSRI to SSRI) or to a different class (SSRI to non-SSRI).18 Some benefits of switching medications compared with augmenting medications are potentially lower costs and less risk of adverse effects, but PCPs must watch for withdrawal symptoms resulting from abrupt discontinuation of the original antidepressant. Strategies utilizing cross-titration of antidepressants may be helpful.

AV 3. Switching and Augmenting Strategies in Depression, Ranked by Efficacy Data (00:43)

Based on Papakostas18
Efficacy rank based on randomized, double-blind, placebo-controlled studies as well as STAR*D, which was not placebo-controlled

Augmenting medications. The most studied augmentation strategy is adding atypical antipsychotics (eg, aripiprazole, olanzapine, quetiapine, risperidone) to antidepressants, but other adjunctive agents used with antidepressants include omega-3 fatty acids, thyroid hormone, and lithium (see AV 3).18 Augmenting the current treatment can maintain the partial therapeutic benefit from the initial treatment as well as avoid withdrawal symptoms. Augmenting can also be used to target side effects of the first-line treatment. However, augmenting antidepressant treatment with atypical antipsychotics has the potential for causing adverse effects including metabolic issues and EPS.18 Other augmenting agents, such as lithium, have established efficacy with TCAs, but less evidence exists for their usefulness with newer agents. PCPs should consider the risk of drug interactions and poor adherence when determining whether or not to augment antidepressant treatment.18


PCPs can effectively treat depression using guidelines to select initial treatment and then monitoring adverse effects and response. Pharmacotherapy for depression includes many classes of antidepressants, while psychotherapy, ECT, and exercise can be effective options for patients who cannot tolerate or do not prefer medication. PCPs may recommend mobile apps for some forms of psychotherapy or exercise. For patients who do not respond to initial treatment, PCPs must be prepared to switch or augment treatment as needed and refer those patients with refractory or severe illness or illness beyond their scope of practice to appropriate specialists.

Clinical Points

  • Follow guidelines to select appropriate initial treatment (pharmacotherapy, psychotherapy, or ECT) for your patients with depression based on symptom severity, comorbid conditions, and patient preference
  • Monitor response, adverse effects, and wellness
  • Switch or augment treatment for patients experiencing suboptimal response or adverse effects
  • Suggest helpful smartphone apps to patients who are interested

Drug List

aripiprazole (Abilify), bupropion (Wellbutrin and others), citalopram (Celexa and others), desipramine (Norpramin and others), duloxetine (Cymbalta), escitalopram (Lexapro and others), fluoxetine (Prozac and others), fluvoxamine (Luvox and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), methylphenidate (Ritalin and others), mirtazapine (Remeron and others), modafinil (Provigil and others), olanzapine (Zyprexa and others), paroxetine (Paxil, Pexeva, and others), phenelzine (Nardil and others), quetiapine (Seroquel and others), risperidone (Risperdal and others), sertraline (Zoloft and others), tranylcypromine (Parnate and others), trazodone (Oleptro and others), venlafaxine (Effexor and others), vortioxetine (Brintellix)


5-HT = serotonin, APA = American Psychiatric Association, CBT = cognitive-behavioral therapy, ECT = electroconvulsive therapy, EPS = extrapyramidal symptoms, IPT = interpersonal therapy, HDRS = Hamilton Depression Rating Scale, MAOI = monoamine oxidase inhibitor, MBCT = mindfulness-based cognitive therapy, MDD = major depressive disorder, PCP = primary care provider, PHQ-9 = 9-item Patient Health Questionnaire, QIDS-SR = Quick Inventory of Depressive Symptomatology-Self-Report, SDS = Sheehan Disability Scale, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, TCA = tricyclic antidepressant, WHO-5 = World Health Organization Well-Being Index

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