Adjunctive strategies for treatment-resistant depression

Second-generation antipsychotics

The value of antipsychotic medications for a select subgroup of depressed patients was recognized shortly following the introduction of medications such as chlorpromazine and thioridazine; the potential for additive benefit in combination with antidepressants was explicitly recognized by the marketing of several proprietary formulations, including amitriptyline plus perphenazine and tranylcypromine plus trifluoperazine. However, by the late 1980s, use of these "first-generation" antipsychotics was largely delimited to treatment of more severely depressed patients, particularly those experiencing psychotic features. This practice changed within a few years of the introduction of risperidone and olanzapine, the first members of the SGA class. The SGAs are now the best proven option for adjunctive therapy following inadequate response to antidepressant therapy of MDD ( ; ; ). In the United States, three SGAs (aripiprazole, quetiapine, and brexpiprazole) are approved by the Food and Drug Administration (FDA) for the broader indication of inadequate response to antidepressants, and a fourth—olanzapine, specifically in combination with fluoxetine—has FDA approval for the stricter classification of treatment-resistant depression (TRD). Yet another SGA, risperidone, has established adjunctive efficacy in controlled trials ( ) even though the manufacturer opted not to seek FDA approval for this indication. As there are positive placebo controlled studies of adjunctive therapy with a number of other SGAs, including ziprasidone ( ), cariprazine ( ) and pimavanserin ( ), it may well be that most if not all of the SGAs has efficacy as adjuncts to antidepressants.

Looking across studies, there are several key clinical observations. First, significant drug placebo differences are routinely observed within the first 2 weeks of adjunctive therapy with SGAs. The SGAs thus have a faster onset of effect than conventional antidepressants. Second, the dose needed to exert such a rapid effect tends to be lower than the minimal dose needed for antipsychotic efficacy in patients with schizophrenia or mania. For aripiprazole, for example, the modal dose for antidepressant responders is 5 mg/day, whereas 15 mg/day is generally considered to be the minimal effective dose for treatment of schizophrenia or mania ( ). Third, unlike conventional antidepressants, the SGAs appear to be comparably effective for patients with or without prominent anxiety symptoms. This observation does not mean that adjunctive SGA therapy is specifically indicated for patients with high levels of anxiety, but does reflect the clinical observation that they are useful for a broad range of patients who do not benefit from antidepressant (see, for example, ). And fourth, although there are marked differences between the various members of the SGA class in terms of side effects and risks of weight gain and other metabolic complications ( ; ), their efficacy—as determined by drug versus placebo differences in RCTs—appears to be roughly comparable.

It may also be that some—if not most—of the SGAs could be antidepressants if prescribed as monotherapy. In this respect, it is noteworthy that the efficacy of quetiapine monotherapy in MDD has been established by multiple RCTs in doses ranging from 50 to 300 mg/day ( ). Although approved for this indication in some countries, the US FDA did not recommend approval of quetiapine monotherapy of MDD because of concerns about side effects and the potential for longer term complications, including tardive dyskinesia. The potential role of SGA monotherapy for a carefully selected subset of depressed patients is underscored by the fact that four members of the class—olanzapine, quetiapine, lurasidone, and cariprazine—have established efficacy for treatment of bipolar depression ( ). In the case of lurasidone, monotherapy efficacy also has been shown in one placebo controlled study of patients with MDD with mixed features ( ).

Although inspection of effect sizes strongly supports the notion that these medications have similar efficacy as adjunctive therapies, it must also be noted that there is a dearth of data from comparative RCTs. Indeed, there is only one placebo controlled RCT in the published literature comparing two SGAs as adjunctive therapies for antidepressant nonresponders ( ). In this trial, 503 MDD outpatients with a history of nonresponse to antidepressant therapy in the current depressive episode as well as nonresponse to a prospective, 8–10 week trial of antidepressant monotherapy were randomized to 6 weeks of double blind adjunctive therapy with brexpiprazole, quetiapine or placebo. At study endpoint, they found that brexpiprazole (titrated to 1–3 mg/day) was efficacious (versus an adjunctive placebo; mean MADRS difference 1.5 points, P < .008), whereas quetiapine (titrated to 150–300 mg/day) was not (mean MADRS difference 0.3 points). One important limitation in the interpretability of this study is that there were no planned comparisons between the two SGAs. In fact, the quetiapine group was included in the design to determine “assay sensitivity” and was only one half the size of the brexpiprazole and placebo groups. Thus, it cannot be said that adjunctive brexpiprazole therapy was significantly more effective than adjunctive quetiapine therapy in this study.

There is also a dearth of studies of the comparative efficacy of SGAs and other clinically relevant options. Only two large scale studies exist, one of quetiapine and the other of aripiprazole, contrasting adjunctive SGA therapy against proven strategies. In the first, randomized 681 outpatients with MDD with a history of antidepressant nonresponse to 6 weeks of open label therapy; about one-third of the sample was switched quetiapine (300 mg/day), one-third received quetiapine as an adjunct (300 mg/day), and one-third received adjunctive therapy with lithium salts (target blood level: 0.6–1.0 mEq/L). The latter intervention was chosen as the existing standard of adjunctive therapy. They found that adjunctive therapy with quetiapine was significantly more effective than the other two options after 4 days of treatment ( P < .01), which is consistent with the notion that this strategy has a more rapid onset of benefit. After 6 weeks of therapy, the adjunctive quetiapine group continued to show a larger effect than the adjunctive lithium group (difference in MADRS scores of 2.32; nominal [unadjusted] P < .05). However, as the primary hypothesis of this study was a strict test of noninferiority, the conclusion was that adjunctive therapy with quetiapine was not inferior to adjunctive lithium therapy. There also did not appear to be a meaningful difference in tolerability between the adjunctive interventions.

In an even larger study ( ), 1522 Veterans with MDD who had not responded to at least one adequate trial of antidepressant monotherapy in the current episode were randomized to up to 36 weeks of treatment with one of three strategies: switch to bupropion, combined therapy with bupropion and the current therapy (typically an SSRI or SNRI) or adjunctive therapy with aripiprazole (dosage titrated from 2 to 15 mg/day). They found adjunctive aripiprazole to be significantly more effective than switching to antidepressant monotherapy with bupropion (week 12 response rates: 74% vs 62%, respectively); comparisons between adjunctive aripiprazole arm and combination antidepressant therapy yielded intermediate differences that generally did not reach statistical significance.

Longer term considerations . Although we are now have more than two decades of experience with some of the older SGAs, there are still some important questions about their use as adjunctive therapies for patients with MDD and it seems likely that these questions will not be answered by clinical trial data ( ). Perhaps most important is the uncertainty about just how long an effective adjunctive therapy be continued. Clinical experience informs us that many patients who respond to adjunctive SGA therapy will relapse if the adjunct is withdrawn during the first few months after response, so a standard of practice has emerged for patients to routinely receive at least 4 to 6 months of adjunctive therapy. The need for a continuation phase of treatment forces clinicians to be vigilant to minimize the hazards of weight gain and other metabolic side effects, which are likely to be cumulative across at least the first 6 months of therapy. At some point of continuation therapy, clinicians also must begin to monitor for signs of treatment-emergent dyskinetic movements. In fact, in one study in which patients who responded to adjunctive aripiprazole (mean dose 10 mg/day) could receive up to 1 year of continuation therapy, 4 of 987 patients (about 0.4%) developed dyskinesias ( ). Importantly, in all four cases the dyskinetic movements first diminished and then ceased after withdrawal of aripiprazole, which suggests that clinician vigilance and ongoing monitoring can have rewarding outcomes. The risk of weight gain in this study (4.4 kg) also was not trivial, with about 37% among the 303 patients who completed a year of adjunctive therapy gaining at least 7% body weight.

There are simply not enough data on longer term adjunctive treatment with SGAs in MDD patients. The study of Brunner and colleagues ( ), a double-blind relapse prevention study that enrolled 444 outpatients with TRD who responded to an 8-week open-label course of olanzapine-fluoxetine combination and who did not relapse across 12 weeks of continuation therapy, is the largest of its kind. They found that, after 20 weeks of treatment, the risk of relapse over the next 6 months of double blind therapy was about 32% for the patients who were withdrawn from olanzapine (double blind) and maintained on fluoxetine monotherapy, compared to 16% among those who continued to take the combination of olanzapine and fluoxetine. One patient in the combined treatment arm developed dyskinetic movements during the 6 months of continued therapy, which suggests a risk of treatment-emergent dyskinesia during longer term olanzapine therapy that is roughly comparable to that reported for aripiprazole. Weight gain was a much larger problem in this trial, with about a 4 kg difference in mean weight at the end of the 6 month trial, accompanied by and subtler changes in selected metabolic parameters, including fasting triglycerides. Moreover, looking across treatment phases, 56% of the patients who received 10 + months of therapy with OFC experienced a weight gain of at least 7% of their pretreatment weight. Although open label data collected during ongoing adjunctive therapy with other SGAs suggests somewhat lower risks ( ), it is clear that careful monitoring of weight and metabolic parameters is indicated during longer therapy.

Lithium salts

The therapeutic effects of lithium salts, principally lithium carbonate and lithium citrate, were recognized for patients with recurrent mood disorders from that outset of the first generation of psychopharmacology. Moreover, lithium—typically in doses of 600–1200 mg/day—was the first adjunctive medication found to be efficacious for antidepressant nonresponders on the basis of multiple placebo controlled studies ( ; ; ). Originally described to have a remarkably rapid onset of benefit (i.e., within 48 h ( )) in patients who had not responded to 3–4 weeks of TCA therapy, subsequent reports suggested that many patients needed a more conventional 6–8 weeks of treatment with serum levels (e.g., 0.5–0.8 mEq/L; see, for example, ). In the first metaanalysis of placebo controlled trials, identified 10 eligible studies and confirmed a meaningful advantage for adjunctive lithium salts as compared to the double blind placebo. With an average benefit estimated as an odds ratio of about 3, Crossley and Bauer’s findings suggested that one might expect up to a 20% advantage over and above placebo-expectancy effects, which would correspond to a number needed to treat of about 5. It is noteworthy that only two of the RCTs included in Crossley and Bauer’s metaanalysis studied patients who were taking SSRIs. Thus, their findings and conclusions may be more relevant to adjunctive therapy of TCAs.

Several subsequent metaanalyses have permitted estimations of benefit to be updated and refined, in part by including several more recent studies, and, in part, by use of newer analytic methods to estimate relative efficacy ( ; ). Zhou and colleagues ( ), for example, found that the average benefit of adjunctive lithium therapy was smaller than originally estimated by Crossley and Bauer (Odds Ratio = 1.56). In terms of the average benefit over and above placebo, an effect of size magnitude would suggest an average benefit of only about 10% absolute advantage, which corresponds to a number needed to treat of about 10. In their network metaanalysis, estimated that the benefit was generally comparable to the estimated effect sizes of the SGAs. Consistent with the findings of the RCT conducted by Bauer and colleagues ( ) discussed earlier, concluded that the tolerability of adjunctive lithium therapy also was comparable to adjunctive SGA therapy across 4–8 weeks of treatment ( Fig. 11.1 ).

Before the introduction of the SGAs, adjunctive lithium therapy was the best-proven adjunctive therapy for patients with difficult to treat depression and was generally considered to be more effective than the major alternative of the era, adjunctive therapy with thyroid hormones ( ). With this question in mind, the STAR*D research project included a head-to-head trial that directly compared adjunctive therapy with lithium carbonate (up to 900 mg/day) and thyroid hormone (triiodothyronine [T ₃ ], up to 50 μg/day)( ). Like all of the STAR*D comparisons, a randomized, open label and rated-blinded design was used to compare the adjunctive therapies across 12 weeks of open label treatment. The study enrolled 142 MDD patients who had not responded to about 6 months of treatment, including a 12 week course of citalopram monotherapy, followed by either a second course of antidepressant treatment (with sertraline, venlafaxine or bupropion) or “augmentation” of citalopram by either buspirone or bupropion. Neither adjunctive therapy was particularly effective, with intent to treat remission rates of 16% and 25%, for lithium and thyroid respectively, across up to 12 weeks of therapy. By contemporary standards, a 9% nominal difference in remission rates in patients with difficult to treat depression would be strongly suggestive of an advantage for thyroid hormone, the STAR*D study suffered from a higher than expected attrition rate and statistical power was not as high as planned. Nevertheless, tests of several secondary outcomes pertaining to acceptability and side effects did reveal significant advantages for the patients who received adjunctive thyroid hormone. The unexpectedly poor showing of adjunctive lithium therapy in STAR*D was not limited to tolerability: prescribers also had problems implementing lithium therapy, with infrequent monitoring of serum levels and a tendency to prescribe lower than recommended lithium doses.

Perhaps heralded by the STAR*D findings but more likely a consequence of prescribers’ growing confidence in the value of combined antidepressant therapy and adjunctive SGA therapy, the role of lithium salts in the management of patients with difficult to treat forms of MDD has diminished over the past 15 years. Nevertheless, there important reasons to continue to consider this time-tested strategy for selected patients, particularly for patients at more advanced levels of treatment resistance. Beyond efficacy in MDD that is comparable to SGAs ( ; ), other potential reasons to consider lithium salts include its utility across phases of treatment for bipolar affective disorder ( ) and its established efficacy for relapse/recurrence prevention for patients with recurrent (unipolar) MDD ( ; ). Of particular relevance to patients with more advanced levels of TRD is prophylactic efficacy of the combination of lithium and the TCA nortriptyline following successful treatment with ECT ( ). Finally, although evidence of lithium’s “antisuicide” effect is largely derived from studies of bipolar disorder ( ), a review conducted under the auspices of the Cochrane Collaboration concluded that this benefit was relevant to all patients with recurrent mood disorders ( ).

Longer-Term Considerations . If effective, adjunctive lithium may be continued for months for relapse prevention or years for maintenance therapy. Later emerging side effects include skin changes (including acne and psoriasis) and weight gain, which may suggest development of hypothyroidism. For this reason, thyroid stimulating hormone (TSH) levels are monitored periodically and, when clinically indicated, on the basis of newly emergent symptoms or side effects. Onset of symptoms such as excessive thirst or polyuria may reflect an impairment of renal concentrating ability, which in turn is a consequence of lithium-induced interstitial fibrosis of the kidneys. This “not uncommon” consequence of years of lithium therapy is arguably the most serious complication of maintenance treatment and, if not addressed, may eventually cause chronic renal failure. Following standards of care developed for maintenance lithium therapy of bipolar disorder ( ; ), periodic monitoring of blood levels and measures of renal function, including electrolytes, plasma BUN and creatinine levels and 24 h urinary creatinine clearance levels are recommended to identify patients at risk for renal complications of adjunctive lithium therapy.