Use of second generation antipsychotics for treatment-resistant major depressive disorder

The past twenty-five years have seen the development of approximately 15 new antidepressant medications. These include selective serotonin reuptake inhibitors (SSRIs); serotonin and norepinephrine reuptake inhibitors (SNRIs); mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA); bupropion, a norepinephrine and dopamine reuptake inhibitor (NDRI); nefazodone, a serotonin antagonist and reuptake inhibitor (SARI); and vilazodone, a serotonin reuptake inhibitor and serotonin_1A partial agonist (SRI/5-HT_1A). The older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO-Is) are still available, but they are used less frequently due to poorer tolerability.

Despite the development of new antidepressant medications, response rates are approximately 60% to 80% for patients with major depressive disorder treated with these agents.¹ Furthermore, it has been estimated that 30% to 45% of patients treated for major depressive disorder show either a partial response or nonresponse to treatment with antidepressant therapy.² While a specific definition does not exist, generally patients who fail two or more adequate antidepressant trials during a depressive episode are considered treatment-resistant.^3,4 The inadequate management of symptoms in these treatment-resistant patients has led researchers to examine alternative medications for the treatment of major depressive disorder.

While the mechanism for their antidepressant effects is unknown, there are several theories on how the second generation antipsychotics (SGAs) improve depressive symptoms. The predominant theories revolve around 5-HT_2A antagonism,^5,6 partial agonist effects on the 5-HT_1A receptor,^7,8 5-HT_2C receptor blockade,^9,10 5-HT₇ antagonist effects,¹¹ and inhibition of the norepinephrine transporter (NET).¹² Because the SGAs are a heterogeneous group of drugs with varied receptor binding, they may not all have the same mechanism of action in treating depressive symptoms.

The interest in using the SGAs for unipolar depressive symptoms stems from their successful use in bipolar depression and major depressive disorder with psychotic features. In recent years, there have been numerous studies conducted to examine the use of these agents to treat unipolar depressive symptoms in patients with major depressive disorder, many of which focused on subjects with treatment-resistant symptoms. The results of these studies have been used as evidence to support their role in treatment guidelines for major depressive disorder.

According to the American Psychiatric Association practice guidelines for the treatment of patients with major depressive disorder, patients who fail to respond adequately to initial antidepressant treatment can be managed with one of the following strategies: optimize the antidepressant dose if maximum daily dose has not been reached, change to another antidepressant, augment the antidepressant with psychotherapy, or augment the antidepressant with other pharmacologic agents or electro-convulsive therapy (ECT).¹³ If the practitioner elects to augment with another agent, the guidelines recommend selecting from antidepressants of another pharmacologic class or from non-antidepressant medications such as lithium, thyroid hormone, or a SGA. While the SGAs are suggested at such an early stage in this treatment algorithm, the guidelines recommend that consideration be given to their disadvantages, including high cost and risk of significant adverse effects, relative to alternative strategies.

The treatment guidelines do not specify which patients would be appropriately treated with antipsychotic augmentation therapy or when to elect this strategy over other more conventional choices. The goal of this article is to review the available evidence regarding the use SGAs in patients with treatment-resistant major depressive disorder and to discuss the subsequent role for these agents based on this evidence.

References were located using Medline. Clinical trials were identified using the following search terms: “depression”, “major depressive disorder”, “antipsychotic drugs”, “aripiprazole”, “quetiapine”, “olanzapine”, “risperidone”, “ziprasidone”, “clozapine”, “paliperidone”, “iloperidone”, “asenapine” and “lurasidone”. The searches were limited to articles published in English and included articles published from January 2000 through November 2013. Studies of bipolar depression and depression with psychotic features were excluded. Twenty-seven clinical trials and two case studies were identified. Two unpublished trials were located through bibliographic scans of all published clinical trials and were available on the manufacturer's website.

Trials have been conducted to evaluate the benefits of adjunctive antidepressant therapy in patients with major depressive disorder with aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone (see Table 1). Most of these studies focused on patients who failed at least one traditional antidepressant trial of adequate dose and duration. There are also case reports of adjunctive use of clozapine and paliperidone. No data are available for iloperidone, asenapine or lurasidone at this time.

Four randomized, double-blind placebo-controlled trials have demonstrated that adjunctive aripiprazole provided improved response in depressive symptoms when patients who failed an antidepressant trial continued their antidepressant therapy.^14–17  Dosing ranged from 2-20 mg/day in these trials, with a mean dose between 10–12 mg/day. Fava et al reported a slight improvement in symptoms that was not statistically significant.¹⁸ Dosing in this trial was 2–5 mg/day, which was lower than with the other studies. The most commonly reported adverse effects with aripiprazole in these trials were akathisia, restlessness, fatigue, somnolence, constipation, dry mouth, and tremors.

Quetiapine and quetiapine XR have been studied as adjunctive therapy in four randomized, double-blind, placebo controlled trials.^19–22  McIntyre et al reported that adjunctive quetiapine produced a significant improvement in depressive symptoms at doses up to 600 mg/day (average daily dose of 182 mg) and that symptom improvement occurred as early as day 7.¹⁹ Garakani et al used doses 100 mg/day in subjects without treatment-resistant depression and did not reproduce this early response.²⁰ The two other placebo-controlled trials showed a more robust response with 300 mg/day than with 150 mg/day of quetiapine XR, but both doses began to show a significant improvement in depressive symptoms at day 8.^21,22 A randomized, single-blind study by Yargic et al also demonstrated significant improvement in depressive symptoms with adjunctive quetiapine compared to an antidepressant alone.²³ Subjects in this trial were not required to fail antidepressant therapy to be included.

In a recent randomized, open-label, active-controlled non-inferiority trial, Bauer and colleagues compared adjunctive quetiapine XR or quetiapine XR monotherapy to adjunctive lithium with patients who had failed their current antidepressant therapy.²⁴ Quetiapine XR was given as a fixed dose of 300 mg/day in both groups, and lithium was dosed to provide therapeutic concentrations of 0.6–1.2 mmol/L. Neither quetiapine intervention was found to be inferior to adjunctive lithium therapy. The most common side effects reported by patients taking quetiapine in these trials included sedation, somnolence, lethargy, fatigue, dry mouth, dizziness, and increased appetite.

Risperidone has been studied as an adjunctive agent to antidepressant therapy in three randomized, double-blind, placebo-controlled trials.^25–27  Mahmoud et al reported a significant improvement in depressive symptoms with adjunctive risperidone 2 mg/day compared to an antidepressant alone.²⁵ Reeves and colleagues measured suicidality in patients who failed to respond to an antidepressant and found that subjects had significantly reduced suicidal ideation when treated with adjunctive risperidone 2 mg/day.²⁶ Remission rates were higher with adjunctive risperidone than with placebo in a study conducted by Keitner and colleagues.²⁷ 

Two similarly designed trials by Rapaport et al and Alexopoulos et al examined the time to relapse in patients with treatment-resistant major depressive disorder.^28,29 Both studies had an open label phase in which subjects were treated with citalopram, followed by an open label phase of treatment with risperidone augmentation. Subjects who achieved symptom resolution in these trials were eligible to enter the double-blind phase that compared the combination of citalopram with adjunctive risperidone to citalopram plus placebo. Time to relapse of depressive symptoms was compared during the double-blind phase. Both trials demonstrated a longer time to relapse with adjunctive risperidone, but statistical significance was not achieved. Risperidone was generally well tolerated in the aforementioned trials. The most commonly reported adverse effects were weight gain, hyperprolactinemia, dry mouth, somnolence and headache.

Three randomized, double-blind, active-controlled trials have been conducted that compare fluoxetine with adjunctive olanzapine to traditional antidepressant medication in patients with treatment-resistant depression.^30–32  Shelton et al and Corya et al found the combination of fluoxetine and olanzapine was not superior in response to traditional antidepressant therapy at endpoint, but they reported depressive symptoms responded earlier with the combination.^30,31 Thase and colleagues found the combination of fluoxetine and olanzapine improved depressive symptoms better than either agent alone at equivalent doses.³² 

In a 76-week open label trial of fluoxetine plus olanzapine, patients with major depressive disorder were monitored for long-term efficacy and safety.³³ No comparator group was used. The study included patients with and without treatment-resistant major depressive disorder. The study reported a significant improvement in depressive symptoms beginning at day 4 and continuing throughout treatment. A sub-analysis of the subjects with treatment-resistant depression showed similar results. Mean weight gain was 5.6 kg, and 31% of subjects had a weight gain of ≥ 10% from baseline. Subjects receiving olanzapine in these trials most commonly reported the side effects of weight gain, somnolence, increased appetite, elevated cholesterol, anxiety, tremor, headache, dry mouth, and asthenia. Weight gain was noted to cause trial discontinuation in some subjects.

Two small open-label trials of adjunctive ziprasidone therapy did not demonstrate significant improvement in depressive symptoms in patients with major depressive disorder who had failed treatment with an antidepressant.^34,35 Ziprasidone was generally well tolerated.

Quante et al published a case series of five ECT-resistant inpatients with depression who were treated with clozapine therapy +/− ECT.³⁶ Two of the subjects had unipolar depression and three had bipolar depression. Some evidence of symptom improvement was reported with clozapine therapy, but tolerability was a major limitation. Four of the five subjects reported severely disruptive side effects, two of which had to discontinue therapy.

A case report by Yang and colleagues describes a patient with dose-limiting side effects with venlafaxine.³⁷ Paliperidone was added to the venlafaxine, and the patient reported an improvement in depressive symptoms, sleep and energy after one week. The patient achieved symptom remission in three weeks and experienced no serious adverse effects.

The only SGAs examined for monotherapy use in major depressive disorder are quetiapine and ziprasidone (see Table 2). Most of the studies of these agents did not include patients with treatment-resistant depression, but they have been included in this review since prescribers may contemplate their use in this population. The evidence does not support the monotherapy use of ziprasidone for depression, but there is a stronger body of data for quetiapine.

Seven clinical trials have been conducted to determine the efficacy of quetiapine XR as a monotherapy agent for managing patients with major depressive disorder.^38–43  In three randomized, double-blind, placebo-controlled trials, subjects receiving quetiapine XR monotherapy experienced a significant improvement in depressive symptoms compared to placebo.^38–40  Significant improvements were seen in the first four to seven days of therapy in these trials. Cutler et al compared quetiapine XR monotherapy to both duloxetine and placebo and found that while both quetiapine and duloxetine were associated with greater symptom improvement compared to placebo, subjects receiving quetiapine had significant symptom improvement as early as 7 days into therapy.⁴¹ As mentioned above, Bauer and colleagues conducted a non-inferiority trial that compared adjunctive quetiapine XR and quetiapine XR monotherapy to adjunctive lithium to treat patients who had failed their current antidepressant therapy.²⁴ In this one trial that focused on patients with treatment-resistant major depressive disorder, neither quetiapine intervention was found to be inferior to adjunctive lithium therapy.

Two unpublished clinical trials have been conducted by Astra-Zeneca, the manufacturer of quetiapine, and are available on their website (www.astrazenecaclinicaltrials.com). The studies examined quetiapine XR monotherapy in patients with major depressive disorder. The AMBER trial compared quetiapine monotherapy to both escitalopram monotherapy and placebo, and neither treatment group produced a significant improvement in depressive symptoms at endpoint.⁴² However, the quetiapine group demonstrated a greater improvement than placebo at 2–4 weeks and escitalopram improved symptoms significantly more than placebo by week 4. The AMETHYST trial was a 52-week placebo-controlled maintenance trial that measured the time to occurrence of a depressive episode.⁴³ Compared to placebo, subjects receiving quetiapine XR monotherapy had a significantly longer time to a depressed event as well as a reduced number of relapses. The most commonly reported adverse effects reported by subjects receiving quetiapine in these trials were sedation, somnolence, dizziness, dry mouth, constipation, headache and weight gain.

One randomized, double-blind, placebo-controlled trial has been conducted to examine the efficacy of ziprasidone monotherapy on depressive symptoms in patients with major depressive disorder.⁴⁴ Response and remission rates were not significantly different between the ziprasidone groups and placebo. Flexible dosing up to 160 mg/day was used. Patients were excluded from the trial if they had failed to experience sufficient symptom relief following more than two antidepressant trials during the current depressive episode. The most commonly reported side effects were sedation and fatigue.

Traditional antidepressants are typically better tolerated than the SGAs and have fewer and less severe adverse effects associated with their use. Treatment with the SGAs carries an increased risk of developing serious adverse effects, including weight gain and other metabolic complications, hyperprolactinemia, tardive dyskinesia, neuroleptic malignant syndrome, and QTc prolongation. As a result, antidepressants remain first line for treating depressive symptoms. However, there are some patients with treatment-resistant depression who need alternative options.

Based on the clinical trials, there is sufficient evidence to consider the use of aripiprazole, quetiapine, risperidone, and olanzapine as adjunctive therapy when treating patients with treatment-resistant major depressive disorder. Currently, there is insufficient evidence to recommend any of the other SGAs for adjunctive treatment. While there is some evidence to support the efficacy of quetiapine as a monotherapy agent for major depressive disorder, it may not be an appropriate alternative for treatment-resistant depression at this time because the data to support its use are very limited.

Dosing appears to have influenced the success of some of the clinical trials and should, therefore, be a consideration when starting one of these agents as adjunctive treatment for major depressive disorder. While the doses of these medications used for treating depressive symptoms are typically lower than those used for psychosis, data from the clinical trials can guide practitioners to ensure that dosing is not suboptimal. Aripiprazole was more successful in trials in which doses 5 mg/day were used. Low doses of quetiapine were also less beneficial, requiring doses to be at least 200–300 mg/day. Doses in successful trials of risperidone were 3 mg/day, but no minimum dose can be established based on the presented data. Adjunctive olanzapine produced optimal effects when dosed at 6–12 mg/day.

While there is sufficient evidence to support the consideration of these four agents as adjunctive therapy to antidepressant medication in patients with treatment-resistant depression, there are still many questions that remain unanswered. Because there are no studies comparing the effects of these medications on depressive symptoms, it is unknown if one SGA is superior to the others in this patient population. Since comparative efficacy is unknown, selection can only be based on side effect profiles and patient-related variables. Due to the limited number of long-term studies, it cannot be determined how long the adjunctive SGA should be prescribed for depressive symptoms.

Perhaps the most relevant question is that of appropriate patient population for these medications. Practitioners are left to wonder which patients and circumstances are the most appropriate for the selection of adjunctive SGAs over traditional alternatives to treat depressive symptoms. Since the risk of serious adverse effects is relatively high compared to conventional antidepressant agents, the SGAs are not appropriate to be used widely in patients with unipolar depression. While the American Psychiatric Association's treatment guidelines allow for their adjunctive use after only one failed antidepressant trial,¹³ this is not and should not be the only option available. More conservative approaches are a better choice for most patients. Based on the evidence from clinical trials, the main notable advantage with the SGAs over alternative treatments appears to be earlier response time. While there is some question as to whether this might be a reflection of improved sleep and/or appetite rather than purely an improvement in mood, this might provide a role for these medications in patients with treatment-resistant major depressive disorder. It may be easier to justify the risk of adverse effects for patients who require a quicker response due to suicidality or impending hospitalization.

Some SGAs such as aripiprazole, quetiapine, olanzapine and risperidone have shown efficacy in treating depressive symptoms when added to antidepressant therapy in patients with treatment-resistant major depressive disorder. However, this benefit needs to be weighed against the risk of potential serious side effects when selecting these agents over more traditional therapy. There are still unanswered questions about the appropriate use of these agents in patients with treatment-resistant depression. Further research is required to guide practitioners in medication selection and duration of treatment. While adjunctive treatment with these agents has a role for a limited number of patients with treatment-resistant depression, SGA monotherapy for major depressive disorder is not suggested at this time.