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Current and Upcoming Adjunctive Therapies for Depression
STAR*D and Beyond: Current and Upcoming Adjunctive Therapies for Depression

Released: October 23, 2024

Expiration: October 22, 2025

Greg W. Mattingly
Greg W. Mattingly, MD
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Key Takeaways
  • As antidepressant medications advance in development, 5 atypical antipsychotics have received FDA approval for adjunctive treatment: quetiapine, olanzapine combined with fluoxetine, aripiprazole, brexpiprazole, and cariprazine.
  • Several new therapies for treating depression are emerging, including kappa opioid receptor modulators, selective glutamate modulators, and NMDA receptor modulators.

STARD*D
More than 20 years ago the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was put forward by the National Institute of Health to evaluate the risks and benefits of various antidepressant treatment courses given systematically in a variety of primary care and psychiatric clinics across the United States. An initial 3-month course of citalopram resulted in approximately 1 in 3 patients achieving remission, with less than 50% demonstrating a clinical response after 3 months of treatment. We unfortunately saw diminishing returns with each successive 3-month treatment course. These successive steps included psychotherapy, switching to a different selective serotonin reuptake inhibitor (SSRI), serotonin–norepinephrine reuptake inhibitor (SNRI), bupropion augmentation, and strategies with lithium, thyroid, and buspirone. Step 2 of treatment achieved a 30% remission, with steps 3 and 4 achieving remission rates of 14% and 11% respectively. Although somewhat disappointing from a clinical perspective, these findings ignited a range of research that evaluated alternative treatment strategies for patients struggling with recurrent depression.  

Combining Monoamine Antidepressants
The Combining Medications to Enhance Depression Outcomes study (CoMed) evaluated whether it was better to begin with a standard monotherapy SSRI vs a combination of SSRI plus bupropion or SNRI plus mirtazapine. This study found remission rates of 39% for escitalopram/placebo, 39% for escitalopram/bupropion, and 38% for venlafaxine/mirtazapine with a 52% response rate for each of the 3 treatment paradigms. Adverse events were higher for the venlafaxine/mirtazapine combination than for escitalopram monotherapy. At 7 months, remission and response rates were not significantly different between any of the 3 treatment choices. 

The clinical pearl from these studies was individual patients have preferential responses to specific monoamine treatment options but, when compared among a group of patients, no single monoamine treatment (SSRI, SNRI, bupropion, or combination treatment) appeared to be more beneficial than SSRI monotherapy.   

Adjunctive Atypicals for Depression
Over the next decade, a series of studies looking at atypical antipsychotic augmentation for standard antidepressants were developed here in the United States and across the world. To date, there are now 5 atypical antipsychotics that have been approved by the FDA for adjunctive treatment of depressive symptoms in combination with a standard monoamine antidepressant. The 5 FDA-approved atypical antidepressants for adjunctive treatment include quetiapine, olanzapine in conjunction with fluoxetine, and the 3 dopamine partial agonists, aripiprazole, brexpiprazole, and cariprazine.

Clinicians pick and choose between these 5 agents based on individual responses and potential wanted and unwanted side effect profiles. Of these 5 medications, quetiapine is predictably sedating and helps with insomnia, anxiety, and agitation but has frequent side effects with somnolence and fatigue. Olanzapine, while highly effective for improving depressive symptoms, is most commonly associated with significant weight gain and metabolic disturbances. 

Aripiprazole was the first dopamine partial agonist approved for adjunctive treatment of depressive symptoms. Aripiprazole, a D2 preferential partial agonist, was associated with less weight gain than olanzapine and less sedation than quetiapine. As a fairly nonsedating medication, aripiprazole was the first augmentation strategy to show that atypical antipsychotics could be effective for depressive symptoms without causing sedation. The next evolution was brexpiprazole, a dopamine partial agonist that combined an even higher affinity for the serotonin 1A receptor than the D2 receptor. Serotonin 1A modulation is known to improve depressive and anxiety symptoms and has the potential to speed response by modulating the serotonin 1A autoreceptor in the dorsal raphe. With a target dose of 2 mg, adjunctive brexpiprazole improved depressive symptoms more than a standard antidepressant. Cariprazine is the newest dopamine partial agonist to receive an adjunctive depression indication. Cariprazine is the only medication with preferential D3 versus D2 partial agonism. With different genetic backgrounds, the D3 receptor is derived from chromosome 3 while the D2 receptor is derived from chromosome 11. In addition to having different genetic backgrounds, the D3 receptor tends to be highly expressed in areas of the brain involved with mood, cognition, reward, and pleasure. Cariprazine is energizing, rather than sedating, which can be beneficial for many patients, but can be associated with dose-related akathisia. Although highly effective and offering unique pharmacologic and side effect profiles, all 5 of these agents are still balanced by their potential risks for metabolic and movement disorder side effects. 

The Glutamate Revolution
The next group of medications researched for residual depression and treatment-resistant patients included a variety of compounds with direct glutamatergic modulation. The first of these was intravenous ketamine which rapidly and reproducibly improved depressive symptoms in patients who had been treatment resistant to standard monoaminergic agents. These rapid and robust benefits led to the study and eventual FDA approval of intranasal esketamine for patients with treatment-resistant depression and major depression with suicidal ideation. Although governed by a Risk Evaluation and Mitigation Strategies (REMS) program that requires 2-hour observation surrounding each esketamine treatment, this treatment has proven beneficial for a variety of patients who have struggled with treatment-resistant depression. The next question in the glutamate development involved the potential use of daily oral glutamate modulation vs intermittent IV or intranasal modulation with ketamine or esketamine, respectively. This led to the development of a combination of bupropion/dextromethorphan that allowed bupropion to slow the metabolism of dextromethorphan to achieve an approximately 60-fold higher therapeutic level and extended the half-life 4- to 5-fold. The combination of 105 mg bupropion sustained release plus 45 mg of dextromethorphan given twice daily was shown to improve depressive symptoms and functional outcomes within the first week of treatment. This combination continues to improve over the next 4 to 6 weeks, with remission rates of 69% at 1 year and nearly 80% of patients reporting improvements in work, home, and social quality of life measures. 

The Exciting New Frontier 
Beyond these currently available agents, several novel agents are currently in development that may be of specific benefit for the individualized treatment of patients with depression. Lumateperone, an agent with 60-fold more serotonin 2A modulation than D2 modulation, is currently approved for both bipolar I and bipolar II depression and has achieved 2 positive clinical trials for depression augmentation. This medication can be associated with initial sedation, but may be beneficial in regards to its lack of weight gain or metabolic side effects and minimal if any movement disorder side effects.

Aticaprant and navacaprant are kappa opioid receptor modulators and appear to be specifically beneficial for individuals with anhedonia. This family of agents modulates the kappa opioid receptors in the amygdala and associated areas that seem to improve aspects of reward, motivation, and joy that are affected by depression and other mental health conditions.

Selective glutamate modulators and agents that modulate intracellular signaling are another exciting new frontier. Agents are currently in clinical phase development that modulate selective subunits of the NMDA receptor, the AMPA receptor, and intracellular enzymes such as mTor. These are involved in the neuroplasticity cascade to promote synaptogenesis and increase the production of neural growth factors. 

All in all, there are now 5 atypical agents approved for adjunctive treatment of depression with the sixth pending FDA approval. In addition, there is the intranasal glutamatergic compound approved for treatment-resistant depression and a daily oral glutamatergic agent approved for individuals with major depressive disorder. 

Your Thoughts?
How likely are you to prioritize one of the newer approved atypical antipsychotics for augmentation, compared to more traditional treatment options? Get involved in the discussion by answering the question and posting a comment below.

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