Peer Reviewed

Review Article

Second-Generation Antipsychotics for Treatment-Resistant Major Depressive Disorder in Primary Care

Hani Raoul Khouzam, MD, MPH

ABSTRACT: Major depressive disorder (MDD) is a disabling psychiatric condition. Although antidepressant medications are the mainstay of treatment, many patients fail to achieve remission with their use. Consequently, a range of augmentation and combination strategies has been used to improve treatment outcomes. Recent evidence has shown that adjunctive therapy with atypical or second-generation antipsychotics (SGAs) could improve and potentiate the beneficial antidepressant effects even in the absence of psychotic symptoms. This review summarizes the SGAs used as augmenting agents for the treatment of resistant MDD and the pharmacologic mechanisms involved in this combined treatment approach. Primary care providers using SGAs to treat MDD must monitor patients for certain adverse effects such as weight gain and hyperglycemia.

KEYWORDS: Major depressive disorder, atypical antipsychotics, second-generation antipsychotics, treatment-resistant depression, primary care.

Major depression is a psychiatric condition that causes substantial disability that can exceed that of other chronic conditions such as heart disease and diabetes.1 The mainstay of treatment for depression and depressive episodes in primary care usually is prescribing a medication from among the many classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), norepinephrine-dopamine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and atypical or novel antidepressants, as well as older classes such as tricyclic antidepressants, or monoamine oxidase inhibitors.

Despite the availability of all of these antidepressants, up to 70% of patients with major depressive disorder (MDD) do not respond to or achieve remission with antidepressant treatment, and many experience long-term persistent and disabling depressive symptoms.2,3 According to a clinical practice guideline from the American College of Physicians,4 patients with MDD who do not respond or who achieve only partial response to antidepressant treatment after 4 to 8 weeks require a change in antidepressant dose, a switch to another antidepressant, or treatment with augmenting therapies. Patients with MDD who do not respond adequately to trials of antidepressants usually are classified as having treatment-resistant depressive disorder (TRD) and require augmentation strategies.5

Traditional augmentation treatment with lithium or thyroid hormones is not supported by evidence-based data and has never received approval from the US Food and Drug Administration (FDA). An augmentation strategy with the atypical antipsychotics or second-generation antipsychotics (SGAs) has been shown to be beneficial by enhancing the effects of antidepressant medications, improving depression remission rates, and minimizing antidepressant-mediated adverse effects.6 As a result, the FDA approved the SGAs aripiprazole, quetiapine extended-release (XR), olanzapine, and the combined formula of olanzapine plus fluoxetine as augmenting agents for patients with TRD.

Other SGAs such as ziprasidone, asenapine, iloperidone, and lurasidone have demonstrated their beneficial augmentation effects in TRD in several clinical trials and have been used in clinical practice; however, they have not been FDA-approved and are not included in this review. Table 1 summarizes the SGAs that have been used to treat TRD.

The following is a review of SGAs that have been FDA-approved as augmenting agents for the treatment of TRD.

Aripiprazole Augmentation

Rationale for use in TRD. The clinical benefit of adjunctive aripiprazole for treating patients with TRD has been explored in several studies.7-9

Pharmacology and dosing. Aripiprazole acts as a partial agonist at dopamine D2 receptors. It also is a partial serotonin 5-HT1A receptor agonist, and an antagonist at serotonin 5-HT2A, histamine H1, and α1-adrenergic receptors. Switching patients to aripiprazole should be done slowly because of the medication’s exceptionally high affinity for dopamine D2 receptors, given that it is a partial agonist at this receptor.10

Aripiprazole is available as a standard tablet, an orally disintegrating tablet, a sterile solution for intramuscular (IM) injection, and a long-acting IM formulation for monthly administration. The IM formulations are not used as augmentation therapy for TRD.

Doses could be decreased based on tolerability; patients who are unable to tolerate 5 mg/d could have their dose decreased to 2 mg/d. The recommended initial dose of adjunctive aripiprazole for TRD usually is 2 to 5 mg/d, with a target dose of 5 to 10 mg/d and a maximal dose of 15 mg/d, although some case studies have shown efficacy of aripiprazole augmentation at a dose as low as 3 mg/d.11

Tolerability. Overall, adjunctive aripiprazole was well tolerated in clinical studies.12 The most common adverse effects were headache, nausea, vomiting, insomnia, tremor, and constipation. Weight gain has been minimal in short- and long-term trials. Aripiprazole has a low risk for increased lipid levels or prolactin levels, sedation, and most extrapyramidal symptoms. However, it has an increased risk of akathisia (a feeling of restlessness and an inability to sit still); despite this effect, most participants in clinical trials continued aripiprazole treatment due to its beneficial effects of improving TRD. Moreover, many participants experienced remission of akathisia with dose reduction.12 Aripiprazole has a low risk for causing QT prolongation and torsades de pointes and should be avoided in patients with congenital long QT syndrome.13

Quetiapine XR Augmentation

Rationale for use in TRD. The clinical benefit of adjunctive quetiapine for treating patients with TRD has been reported in several studies.14,15

Pharmacology and dosing. Quetiapine binds with low affinity to a broad range of amine receptors, with no affinity for the muscarinic cholinergic receptors. It has dopamine D2 and serotonin 5-HT2A antagonist activity, and it has preferential activity at histamine H1, α1-adrenergic, and α2-adrenergic receptors.15

Quetiapine XR is available only in the form of an oral tablet.

Systemic quetiapine exposure after orally administered quetiapine XR is similar to that of the immediate-release formulation of quetiapine at the same dosage, although quetiapine XR is absorbed more slowly, and plasma concentrations are more stable over time. Quetiapine XR is recommended at a daily dose of 150 to 300 mg/d. Response rates usually are significantly higher with adjunctive quetiapine XR at 300 mg/d rather than at 150 mg/d; in rare cases, the dose may be raised to 600 mg/d.16

Tolerability. The main adverse effects of quetiapine are sedation, orthostatic hypotension, akathisia, dry mouth, and weight gain.17,18 Sedation most often is noted early in treatment and appears to be more closely related to treatment duration than to dose, so patients may find their sedation improving after several days, even if the medication dose still is being titrated.18 Quetiapine appears to cause fewer extrapyramidal symptoms than do other SGAs.19 Patients’ tolerance to somnolence, sedation, lethargy, and other associated adverse effects also occurs over time.18,19 Quetiapine may cause QT prolongation in the presence of other factors that could prolong the QT interval; thus, its use should be avoided concomitantly with other medications that prolong the QT interval and in patients with risk factors for QT prolongation.20

Olanzapine and Olanzapine-Fluoxetine Augmentation

Rationale for use in TRD. Studies of olanzapine monotherapy and olanzapine in combination with fluoxetine have shown beneficial results for the treatment of TRD.21 Some studies have shown the time to response and remission to be significantly shorter for olanzapine-fluoxetine combination therapy than for fluoxetine and olanzapine monotherapies, suggesting that the combination has a more rapid onset of action.22

Pharmacology and dosing. Olanzapine has a 2-fold greater affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors. Olanzapine also blocks other receptors, including muscarinic, histaminic, α1-adrenergic, D1, and D4 receptors. Fluoxetine is an SSRI that prevents serotonin, norepinephrine, and dopamine transport. It also synergistically increases the release of norepinephrine, dopamine, and serotonin when combined with olanzapine.22

The starting dose of olanzapine usually is 5 to 10 mg/d. Maintenance doses of 15 to 30 mg/d are common, and doses of up to 40 mg/d can be useful in select cases, despite that this exceeds the recommended maximum of 20 mg/d. Doses for most patients who respond to the drug should not exceed 20 mg/d, because research data have suggested equivalent efficacy of 10, 20, and 40 mg/d but worsened tolerability at doses of 40 mg/d compared with 10 mg/d.23

Olanzapine is available as a standard tablet, an orally disintegrating tablet, a sterile solution for IM injection, and a long-acting IM formulation for monthly administration. The IM formulations are not used as augmentation for TRD.

Olanzapine-fluoxetine combination is available only as oral capsules, in doses from 25 mg fluoxetine plus 6 mg olanzapine per day to 50 mg fluoxetine plus 12 mg olanzapine per day, not exceeding 75 mg fluoxetine and 18 mg olanzapine per day.24

Tolerability. Olanzapine and olanzapine-fluoxetine are relatively well tolerated. The most frequently reported significant adverse events are somnolence, increased appetite, asthenia, weight gain, headache, dry mouth, nausea, anxiety, tremors, and nervousness.25,26 Olanzapine-fluoxetine combination therapy may have a rapid, robust, and sustained antidepressant effect, which can be an important factor in treatment choice, particularly in patients with suicidal ideation.22


Although the SGAs can be effective therapies for TRD, they often lead to the development of adverse effects, especially in the geriatric population.10 The potential dose-limiting adverse effects of SGAs are summarized in Table 2. Tardive dyskinesia also can occur with SGAs, the long-term adverse effects of which are outlined in Table 3.

The recommendations for monitoring patients starting on SGAs, according to an expert panel on antipsychotic drugs and diabetes and obesity,27 are listed in Table 4. Clinical intervention and consideration of weight-reduction programs should be initiated for a 5% or greater increase in weight, a point increase in body mass index, and a 1-inch or greater increase in waist circumference, which are the criteria for the development of metabolic syndrome (Table 5).28

Primary care providers must be aware of the black box warning regarding an increased risk of death associated with the use of SGAs, particularly in elderly patients with dementia-related psychosis. Although the causes of death in clinical trials varied, most appeared to be either cardiovascular (eg, heart failure, sudden cardiac death) or infectious (eg, pneumonia). It still is unclear whether the increase in mortality is directly related to the effects of SGAs or whether it can be attributed to patient characteristics. The increased risk of suicidal thinking and behavior observed in short-term studies of children and adolescents with MDD taking antidepressants has prompted another black box warning; thus, this patient population requires close monitoring for clinical worsening, suicidality, or unusual changes in behavior.

In light of the challenge that the treatment of TRD poses to primary care clinicians, patients, and their families, augmentation of antidepressants with the FDA-approved SGAs aripiprazole, quetiapine, olanzapine and olanzapine-fluoxetine appear to be therapeutically indicated.

Hani Raoul Khouzam, MD, MPH, is the medical director of employee behavioral health at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, and a professor of psychiatry at Dartmouth Geisel School of Medicine in Hanover, New Hampshire.


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