Antidepressant-resistant major depressive disorder (AR-MDD) poses significant challenges in psychiatric treatment.
Antipsychotics like aripiprazole (ARI) and brexpiprazole (BRE) have emerged as effective adjunct therapies that may be more tolerable than older antipsychotics.
Highlights:
- Both Brexipiprazole and Aripiprazole demonstrated better efficacy than placebo in treating AR-MDD in Japanese patients.
- Brexipiprazole showed a higher discontinuation rate due to adverse events, while Aripiprazole reported a higher incidence of at least one adverse event.
- Brexipiprazole and Aripiprazole were associated with an increased risk of akathisia and weight gain.
- An initial dose adjustment of Brexipiprazole may reduce the risk of adverse events like akathisia.
Source: Neuropsychopharmacology Reports (2024)
History & Medical Uses: Brexpiprazole vs. Aripiprazole
Brexpiprazole (BRE)
Historical Development
- Brexpiprazole, developed by Otsuka Pharmaceutical and Lundbeck, is a relatively newer antipsychotic medication. It was approved by the U.S. Food and Drug Administration (FDA) in 2015.
- The development of BRE was part of the ongoing search for more effective treatments for psychiatric disorders with fewer side effects. It was designed to provide better tolerability and a lower risk of certain side effects compared to older antipsychotics.
Common Uses
- Schizophrenia: BRE is primarily used for the treatment of schizophrenia. It helps in managing symptoms like hallucinations, delusions, and thought disorder.
- Major Depressive Disorder (MDD): It is also approved as an adjunctive therapy for major depressive disorder, especially in cases where patients have not responded adequately to antidepressant treatment alone.
- Other Uses: While not officially approved for these indications, BRE may sometimes be used off-label for other mental health conditions, based on the clinician’s judgment.
Aripiprazole (ARI)
Historical Development
- Aripiprazole was developed by Otsuka Pharmaceutical and was first approved by the FDA in 2002. It represented a significant advancement in antipsychotic medication, being one of the first of the “third-generation” antipsychotics.
- ARI’s development was marked by the goal to create a medication that could effectively treat psychotic symptoms while minimizing side effects like motor disturbances and metabolic issues, common with earlier antipsychotics.
Common Uses
- Schizophrenia: ARI is widely used in the treatment of schizophrenia, effective in managing both positive and negative symptoms.
- Bipolar Disorder: It is also approved for the treatment of manic and mixed episodes associated with bipolar disorder.
- Major Depressive Disorder: ARI is used as an adjunct treatment for MDD, particularly in patients who have not achieved sufficient relief with antidepressants alone.
- Irritability in Autism Spectrum Disorders: In pediatric patients, ARI is sometimes prescribed to address irritability and aggression in autism spectrum disorders.
- Tourette Syndrome: It is also used for the treatment of Tourette syndrome.
- Off-label Uses: Like BRE, ARI is sometimes used off-label for other psychiatric conditions, including anxiety disorders and obsessive-compulsive disorder (OCD), based on the clinician’s discretion.
Which Patients Might Benefit from Brexpiprazole (BRE) or Aripiprazole (ARI) for Depression?
In the context of treating depression, specifically Major Depressive Disorder (MDD), it’s crucial to understand which patients might benefit most from the addition of BRE or ARI to their treatment regimen.
1. Patients with Treatment-Resistant Depression
Individuals Not Responding to Standard Antidepressants: BRE and ARI can be particularly effective for patients who haven’t achieved satisfactory results with traditional antidepressants.
Patients with Partial Response to Treatment: Those who have experienced some improvement but not complete remission with their current antidepressant regimen.
2. Patients with Specific Depressive Symptoms
Persistent Anhedonia and Low Mood: Individuals struggling with persistent feelings of sadness or inability to enjoy activities may find these medications beneficial.
Cognitive Symptoms: Some patients with MDD experience cognitive symptoms (like difficulty concentrating) that are not fully addressed by antidepressants alone. BRE and ARI might offer additional relief.
3. Considering Side Effect Profiles in Depression
Tolerability of Side Effects: Patients who may be sensitive to the side effects of other antipsychotics or antidepressants might prefer BRE or ARI, considering their relative side effect profiles.
Concerns Over Specific Side Effects: Those who are particularly concerned about certain side effects (such as extrapyramidal symptoms or sexual dysfunction) might consider these medications after consulting their healthcare provider.
4. Patients Seeking Additional Therapeutic Benefits
Augmentation Strategy:Patients for whom a combination therapy approach has been recommended to enhance the effectiveness of their current antidepressant treatment.
Desire for a Balanced Neurotransmitter Modulation: Individuals interested in medications that offer a more nuanced approach to neurotransmitter modulation than typical antidepressants.
Brexipiprazole & Aripiprazole (Mechanisms of Action in Depression)
The effectiveness of Brexpiprazole (BRE) and Aripiprazole (ARI) in treating depression, particularly as adjunct therapies in Major Depressive Disorder (MDD), is closely linked to their unique mechanisms of action.
These mechanisms are thought to contribute to their antidepressant effects.
Brexpiprazole (BRE)
Serotonin-Dopamine Activity Modulation
BRE is known as a serotonin-dopamine activity modulator.
This means it acts on both serotonin and dopamine receptors, two key neurotransmitters involved in mood regulation.
Partial Agonist at Dopamine D2 & Serotonin 5-HT1A Receptors
As a partial agonist at these receptors, BRE moderately activates them.
This action is thought to help stabilize dopamine and serotonin levels in the brain, which can be beneficial in treating mood disorders.
Antagonist at Serotonin 5-HT2A Receptors
BRE also acts as an antagonist at 5-HT2A receptors.
Blocking these receptors is believed to contribute to antidepressant effects, as overactivity at these sites has been associated with depressive symptoms.
Balancing Neurotransmission
The combined agonist and antagonist actions of BRE are believed to help balance neurotransmitter levels in the brain, leading to improvements in mood, emotional regulation, and cognitive symptoms associated with depression.
Aripiprazole (ARI)
Partial Agonist at Dopamine D2 & Serotonin 5-HT1A Receptors
Similar to BRE, ARI is a partial agonist at D2 and 5-HT1A receptors.
This mechanism helps in modulating dopamine and serotonin levels, which are crucial in mood regulation and depressive symptoms.
Antagonist at Serotonin 5-HT2A Receptors
ARI’s antagonistic action at 5-HT2A receptors can mitigate depressive symptoms.
Blocking these receptors is thought to have a positive effect on mood and anxiety symptoms.
Dopamine Stabilization
ARI’s partial agonistic activity at D2 receptors helps stabilize dopamine levels, addressing both the deficit and excess of dopamine in different brain areas.
This is significant because dopamine dysregulation is often observed in depression.
By modulating dopamine and serotonin without fully blocking these receptors, ARI can potentially reduce some of the side effects often seen with other antipsychotics, such as motor symptoms or extreme sedation, which can be beneficial in patients with depression.
Brexipiprazole (BRE) vs. Aripiprazole (ARI) for Major Depression (2024 Comparison Study)
Kish et al. aimed to assess the efficacy, acceptability, tolerability, and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) in Japanese patients with antidepressant-resistant major depressive disorder (AR-MDD).
A thorough network meta-analysis was conducted to compare these antipsychotic drugs, providing crucial insights for clinical practice.
This comparison is particularly relevant given the increasing prevalence of AR-MDD and the need for effective adjunctive therapies.
Methods
The study was structured as a systematic review and network meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
The inclusion criteria focused on randomized, double-blind, placebo-controlled trials involving Japanese AR-MDD patients treated with BRE or ARI.
Various outcome measures were assessed, including depression severity scales, response and remission rates, all-cause discontinuation, and side effects like akathisia and weight gain.
Results
The meta-analysis included three clinical trials with a total of 1736 participants.
Both BRE and ARI were more effective than placebo.
However, BRE showed a higher rate of discontinuation due to adverse events, whereas ARI had a higher incidence of at least one adverse event.
Both medications were associated with increased risks of akathisia and weight gain.
Notably, no significant differences in efficacy or safety were found between BRE and ARI.
Limitations
One key limitation was the small number of studies, which could limit the generalizability of the findings.
The lack of direct comparisons between BRE and ARI in the included studies meant that the results primarily provided indirect evidence.
Additionally, the study did not investigate the relationship between blood concentrations of the medications and their efficacy or safety profiles, which could be a crucial factor in understanding their impact.
In conclusion, this study provides valuable insights into the use of BRE and ARI for Japanese patients with AR-MDD, highlighting their efficacy and distinct safety profiles.
The findings underscore the importance of personalized treatment approaches, considering individual patient responses and potential side effects.
Detailed Results: Brexipiprazole vs. Aripiprazole (Comparison Study)
The results of this network meta-analysis provide a nuanced understanding of the efficacy and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) in treating Japanese patients with antidepressant-resistant major depressive disorder (AR-MDD).
Efficacy vs. Placebo
- Effectiveness: Both BRE and ARI were found to be more effective than placebo in improving symptoms of AR-MDD. This was evidenced by better scores on the Montgomery Åsberg Depression Rating Scale, the Clinical Global Impression severity scale, and social functioning scales.
- Response and Remission Rates: ARI demonstrated lower non-response and non-remission rates compared to placebo, a result not mirrored by BRE.
Safety & Tolerability
- Discontinuation Rates: BRE showed a higher rate of discontinuation due to adverse events compared to placebo, highlighting issues with tolerability. In contrast, ARI did not exhibit this trend.
- Incidence of Adverse Events: ARI reported a higher incidence of at least one adverse event when compared with the placebo, raising concerns about its overall safety profile.
- Specific Side Effects: Both medications were associated with an increased risk of akathisia and weight gain, side effects significant enough to warrant consideration in clinical decision-making.
Comparison Between BRE & ARI
- Lack of Significant Differences: Interestingly, there were no significant differences observed between BRE and ARI across most of the outcomes. This suggests that, in terms of overall efficacy and safety, the two drugs may be broadly comparable for this patient population.
What are the implications of this study?
The findings of this study have several important implications for the treatment of AR-MDD, particularly in the Japanese context.
Clinical Decision-Making
- Personalized Treatment Plans: The differential safety profiles of BRE and ARI underscore the need for personalized treatment approaches. Clinicians should consider individual patient histories and potential risk factors when choosing between these medications.
- Monitoring and Management of Side Effects: Given the increased risks of akathisia and weight gain, regular monitoring for these side effects is crucial. Adjustments to dosage or switching medications may be necessary for some patients.
Pharmacological Insights
- Dose Adjustments: The study suggests that starting with a lower dose of BRE might reduce the risk of adverse events like akathisia. This could be particularly relevant for populations with specific genetic or metabolic profiles, such as the Japanese.
- Understanding Drug Mechanisms: The similar efficacy of BRE and ARI, despite their different pharmacological profiles, offers an interesting avenue for further research into how these drugs interact with the neurobiological pathways involved in AR-MDD.
Research & Development
- Further Studies on Dosing & Ethnic Variability: The study highlights the need for more research into how dosing strategies and ethnic differences affect the efficacy and safety of psychiatric medications.
- Direct Comparisons of BRE & ARI: Future research should aim to directly compare BRE and ARI in diverse populations to provide clearer guidance on their use in AR-MDD.
Policy & Guidelines
- Updating Treatment Protocols: The results could inform updates to clinical guidelines for treating AR-MDD, particularly in Japan. Emphasizing the importance of considering side effect profiles and patient-specific factors could enhance treatment outcomes.
Risks of Using Brexpiprazole (BRE) or Aripiprazole (ARI) for Depression
While Brexpiprazole (BRE) and Aripiprazole (ARI) can be effective in treating depression, especially as adjunct therapies, they come with certain risks.
These risks often justify the consideration of other medications as first-line treatments.
Understanding these risks is crucial for making informed treatment decisions.
1. Side Effects
Metabolic Changes: Both BRE and ARI can lead to metabolic changes, including weight gain, increased blood sugar, and altered lipid profiles.
Movement Disorders: Although less common compared to other antipsychotics, there is still a risk of extrapyramidal symptoms (EPS), including tremors, restlessness, and potentially tardive dyskinesia.
Sedation and Fatigue: Patients may experience sedation or fatigue, which can impact daily functioning.
Gastrointestinal Issues: Nausea, constipation, and other gastrointestinal problems can occur.
2. Potential for Overmedication
Using BRE or ARI as adjuncts to standard antidepressants increases the complexity of the medication regimen, potentially leading to overmedication, especially in patients with milder forms of depression.
3. Risk of Aggravating Symptoms
In some cases, antipsychotics can paradoxically exacerbate depressive symptoms or induce emotional blunting or apathy.
4. Long-Term Dependency & Withdrawal
Long-term use of these medications can lead to dependency, and discontinuation might result in withdrawal symptoms or relapse of depressive symptoms.
5. Interactions with Other Medications
BRE and ARI can interact with other medications, potentially leading to adverse effects or reduced effectiveness of one or more of the drugs involved.
Takeaway: Brexipiprazole & Aripiprazole for Major Depression
In summary, Brexipiprazole and Aripiprazole are valuable options for individuals with AR-MDD, especially for those who haven’t found sufficient relief with standard antidepressants.
Their unique mechanisms of action and potential for a more favorable side effect profile make them appealing choices for a subset of patients with depression.
As always, the decision to use these medications should be made in consultation with a healthcare provider, considering the individual’s specific symptoms, medical history, and treatment goals.
References
- Paper: Comparison of brexpiprazole, aripiprazole, and placebo for Japanese major depressive disorder: A systematic review and network meta-analysis (2024)
- Authors: Taro Kishi et al.