January/February 2024

Mental Health: Treatment-Resistant Depression
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 17 No. 1 P. 8

Major depressive disorder affects one in five individuals and is the leading cause of disability worldwide.1 Antidepressants are first-line treatment for adults with moderate to severe depression, with about 70% of persons achieving complete remission.2 However, at least 30% of people fail to respond adequately, even after several months and numerous treatment attempts. Those who do not achieve an adequate response to two separate antidepressant medications are considered to have treatment-resistant depression (TRD)—or difficult to treat depression. TRD can be devastating to patients and contributes to increased morbidity and challenges with functional and social activities while also increasing mortality from all causes, including a greater risk of suicide. TRD treatment is challenging and typically requires augmenting an antidepressant with another agent, such as lithium, triiodothyronine (T3 thyroid hormone), and, more recently, second-generation antipsychotics (SGAs). Even with the addition of adjuvant agents, only 30% of patients will achieve remission.3

Consequences
Persons with TRD are at risk of significant impairments to cognitive functioning and challenges that can negatively affect family, social, and work-related outcomes.4 A study comparing patients with TRD episodes to patients with major depressive disorder and no TRD episodes found that those with TRD have a higher prevalence of psychiatric comorbid conditions (anxiety, stress sleep disorder, and substance use disorder), twice the utilization of outpatient health care resources, three times the number of inpatient bed days, and a 23% higher all-cause mortality rate, and were four times more likely to cause intentional self-harm.5 The risk of suicide is a tremendous concern, with another study finding that 17% of persons with TRD episodes had attempted suicide.6

Risk Factors
Researchers identified several clinical factors predicting an increased risk for TRD.7 Using a Montgomery and Åsberg Depression Rating Scale (MADRS), TRD was defined using a score ≥22 after at least two antidepressant trials. The response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Statistical analysis was used to replicate predictors of treatment and outcome for TRD among 16 clinical variables in 916 patients. The most prominent risk factors that significantly increased the risk of TRD include the following:

• symptom severity (odds ratio (OR) = 3.31);
• psychotic symptoms (OR = 2.52);
• suicidal risk (OR = 1.74);
• generalized anxiety disorder (OR = 1.68);
• inpatient status (OR = 1.65);
• a higher number of antidepressants administered previously (OR = 1.23);
• lifetime depressive episodes (OR = 1.15); and
• longer duration of the current episode (OR = 1.022).

Another study found that patients who developed TRD were younger and more likely than patients with no TRD to suffer from fatigue, substance use disorders, anxiety, other psychiatric conditions, insomnia, and pain.8

Patient compliance is also a risk factor since not staying on an antidepressant long enough and skipping doses can hinder the drugs’ effectiveness.9 Patients should be made aware that it may take six to eight weeks to achieve full effects of antidepressants. They should also be made aware that many side effects, such as nausea, constipation, diarrhea, dry mouth, dizziness, and bad taste in the mouth, often improve over time.

Pharmacological Treatment of TRD
Treatment of TRD typically involves augmentation of therapy by adding a second medication, not usually considered an antidepressant on its own, to a first-line antidepressant pharmacotherapeutic option such as selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors.

Second-Generation Antipsychotics
With the increased availability and marketing of newer SGAs or “atypical antipsychotics,” there’s been increased interest in and use of antipsychotics as adjuncts for the treatment of TRD. Several SGAs have been approved by the FDA as add-on therapy for the treatment of TRD, including aripiprazole, brexpiprazole, cariprazine, extended-release quetiapine, and olanzapine-fluoxetine combination. Other SGAs are used off-label. SGAs are serotonin-dopamine receptor antagonists, as opposed to older first-generation or “conventional” antipsychotics such as haloperidol, which are primarily dopamine receptor antagonists.

For TRD, evidence suggests that augmentation with atypical antipsychotics may be appropriate for some patients. However, there are no good head-to-head studies that demonstrate clearcut evidence for the use of one atypical antipsychotic over the other. Also, while antipsychotics may have antidepressant activity, they are not considered appropriate for monotherapy for depression. They should be used as adjuncts to traditional antidepressant medications for persons who fail to respond adequately to an antidepressant alone.

Mechanism of Action
At clinically effective doses, atypical antipsychotics provide antidepressant effects as a result of increased serotonin activity through extensive blockade of serotonin-2A 2A receptors, direct or indirect stimulation of serotonin-1A receptors, and, to a lesser extent, reduction in dopamine-D2 receptor-mediated neurotransmission.10 SGAs other antidepressant effects involve regulation of monoamine, glutamate, gamma-aminobutyric acid, cortisol, and neurotrophic factors.11 In combination with traditional antidepressants, these effects on multiple receptors may improve depression symptoms for some patients.

Studies
In one study, researchers evaluated the number needed to treat (NNT) and number needed to harm (NNH) when adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes.12 They found that several atypical antipsychotics may be helpful as adjuncts to antidepressants. However, lithium was somewhat more effective and better tolerated. Analysis for the study involved 49 drug-placebo pairs. For NNT, SGAs had an NNT of 11 and were more effective than placebo. However, esketamine (NNT = 7) and lithium (NNT = 5) were more effective than SGAs. The study also provided NNT for individual antipsychotics including aripiprazole, olanzapine/fluoxetine, risperidone, ziprasidone, quetiapine, brexpiprazole, and cariprazine. The antipsychotics aripiprazole, olanzapine/fluoxetine, risperidone, and ziprasidone all were more effective (all NNT < 10) than quetiapine (NNT = 13) brexpiprazole (NNT = 16), or cariprazine (NNT = 16). The risk of adverse effects with antipsychotics was high, with an overall NNH = 5.

Quetiapine had the highest risk (NNH = 3), while brexpiprazole was one of the least helpful but had a safer side effect profile with NNH = 19. The NNH for esketamine was 5, while lithium had an NNH of 9. Overall, the risk-to-benefit ratio (NNH/NNT) was much more favorable for lithium, with a ratio = 1.80 compared with ketamine = 0.71 and SGAs = 0.45.

Lithium’s favorable risk-to-benefit ratio may come as a surprise to many as the drug is underutilized, likely due to a lack of understanding about lab monitoring needs, safety data, marketing of newer antipsychotic agents by pharmaceutical companies, and the misperception that SGAs are a safer alternative. Of particular value is that lithium offers clear advantages over many other adjuvants due to its ability to reduce suicidal behaviors.

In another study of antipsychotics, researchers conducted a Cochrane review of studies with patients with TRD receiving augmenting therapy with SGAs.13 They found that while antipsychotics can be effective, their benefits may be offset by an increased number of people who stop using the medication (dropouts). The most common reason for dropouts was side effects. SGAs’ side effects include weight gain, metabolic dysfunction, extrapyramidal symptoms, and tardive dyskinesia. There are also concerns that augmentation with newer antipsychotics in nonelderly patients with depression may be associated with increased mortality risk.14 The Cochrane review noted that most studies looked at the effects of adding an antipsychotic (cariprazine, quetiapine, ziprasidone, or olanzapine) to current antidepressant treatment. These studies suggest that adding cariprazine results in a small reduction in depressive symptoms, adding quetiapine reduces depressive symptoms, and adding ziprasidone probably results in a small reduction in depressive symptoms. Adding quetiapine to antidepressant therapy reduces symptoms below the remission threshold (NNT = 9). At the same time, the number of people who stop using the medicine (dropouts) increases only at the highest dosage > 200 mg/day. Augmentation with cariprazine or ziprasidone improves the clinical response; however, increased dropouts offset the benefit. While olanzapine may reduce depressive symptoms, its effects on dropping out were uncertain due to there only being one small study for review.

Final Considerations
Patients with TRD can experience profound hopelessness with symptoms that often last for many months. For these patients, there’s an obvious need for newer treatment options, such as SGAs for TRD, although there may be good evidence for practitioners to revisit the use of lithium. At first glance, the studies evaluating the benefits of adjunctive therapies, including SGAs for TRD, may not appear to be that impressive; however, keep in mind that these results are in persons with difficult-to-manage depression symptoms where multiple therapies have already failed. Augmenting first-line antidepressants with newer atypical antipsychotics may be a viable option for some patients. While adding adjunctive SGAs may not result in complete remission for all patients, they may benefit some patients significantly. At the same time, using SGAs is not without risk, and patients should fully understand the potential benefits and risks.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
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12. Vázquez GH, Bahji A, Undurraga J, Tondo L, Baldessarini RJ. Efficacy and tolerability of combination treatments for major depression: antidepressants plus second-generation antipsychotics vs. esketamine vs. lithium. J Psychopharmacol. 2021;35(8):890-900.

13. Davies P, Ijaz S, Williams CJ, Kessler D, Lewis G, Wiles N. Pharmacological interventions for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2019;12(12):CD010557.

14. Gerhard T, Stroup TS, Correll CU,et al. Mortality risk of antipsychotic augmentation for adult depression. PLoS One. 2020;15(9):e0239206.