TAP Psychopharmacology Bulletin - New Horizons / 2025 November

Brilaroxazine, developed by Reviva Pharmaceuticals, has recently attracted significant attention as a promising antipsychotic agent for the treatment of schizophrenia. The molecule exhibits a broad pharmacological profile, acting on dopamine, serotonin, norepinephrine, and histamine receptors, thereby demonstrating therapeutic potential for both positive and negative symptoms. This multi-receptor targeting provides a pharmacodynamic advantage that distinguishes it from currently available antipsychotics. The recently published open-label extension (OLE) study has yielded important findings regarding the long-term efficacy and safety of brilaroxazine. Participants in the study demonstrated significant improvements in total Positive and Negative Syndrome Scale (PANSS) scores, along with notable reductions in depressive symptoms and enhanced overall functioning. These results suggest that the drug may target not only psychotic symptoms but also co-occurring affective manifestations.

One of the most remarkable findings is Brilaroxazine’s favorable side-effect profile. Clinical trials have shown minimal association with weight gain, sedation, or extrapyramidal symptoms.

This characteristic represents a key advantage for improving patient adherence in chronic conditions such as schizophrenia, which require long-term pharmacotherapy. Furthermore, no adverse effects have been observed on cardiac safety parameters, including QTc prolongation. Overall, Brilaroxazine presents a balanced profile in terms of both efficacy and tolerability. The drug’s clinical development has reached a critical milestone with the upcoming End-of-Phase 3 meeting with the FDA, which will serve as the primary determinant for its regulatory submission.
If the approval process proceeds successfully, Brilaroxazine may offer new therapeutic options not only for schizophrenia but also for other psychiatric disorders such as bipolar disorder, major depressive disorder, and attention-deficit/hyperactivity disorder (ADHD). Reviva Pharmaceuticals is planning additional hase trials to explore these expanded indications. To date, Brilaroxazine’s pharmacological characteristics and clinical evidence distinguish it as a truly next-generation antipsychotic candidate. Its low burden of side effects may increase its potential as an alternative option for treatment-resistant cases.
The forthcoming period will determine how this molecule will position itself within psychiatric practice. Upon FDA approval, Brilaroxazine is expected to make a significant impact in both clinical and academic psychiatry.

Dr. Gözde Çolak
DOI: 10.1007/asdere_55214_2023_416

Onfasprodil Shows Promise in Treatment-Resistant Depression

Treatment-resistant depression (TRD), defined as failure to respond to at least two adequate antidepressant trials, affects approximately one-third of individuals with major depressive disorder.
A multicenter phase 2 randomized, placebo-controlled study published in The Journal of Clinical Psychiatry investigated the efficacy of onfasprodil (MIJ821), a novel NMDA NR2B subunit antagonist.

In Bipolar Affective Disorder, the majority of the disease burden arises from depressive episodes, which account for approximately two-thirds of the illness duration. Moreover, chronic and subthreshold depressive symptoms are frequently observed even outside acute episodes. The treatment of bipolar depression remains challenging, and current clinical guidelines provide more limited recommendations compared with those for manic episodes and maintenance therapy. In view of these challenges we had the opportunity to interview Prof. Dr. Mehmet Çağdaş Eker and to obtain his views.

ÖD: We often see that many patients with bipolar depression were initially followed under diagnoses of unipolar depression or treatment-resistant depression. In the differential diagnosis process, which clinical clues or historical details can be decisive in clarifying the diagnosis?

MÇE: Bipolar Disorder is generally an illness dominated by depression. For this reason, patients most often present to physicians during depressive periods. Moreover, our patients do not describe episodes of mania because they do not consider them to be an illness. If I were to select three features that would raise suspicion for bipolar disorder during a depressive episode, first would be an increased need for sleep. A history of depression or another psychiatric disorder after childbirth, and a family history of bipolar disorder, would be the other features.

ÖD: According to DSM-5, depression with mixed features is defined within both unipolar and bipolar frameworks. In your view, how well does the definition of mixed symptoms in unipolar depression match real-world clinical populations?

MÇE: I believe that mixed-feature depression also falls within the bipolar spectrum and should be treated like bipolar disorder. However, the diagnostic criteria for mania required in defining mixed-feature depression do not include irritability, psychomotor agitation, or distractibility. This creates difficulties in diagnosing mixed-feature depression and in recognizing the broader bipolar spectrum.

ÖD: Many treatment guidelines recommend agents such as lithium, lamotrigine, quetiapine, and lurasidone as first-line options for bipolar depression. In your clinical practice, what factors determine your choice among them?

MÇE: When treating the acute phase of bipolar disorder, we must plan with long-term medication use in mind. While we expect treatment to alleviate depression rapidly, it must also be sustainable in terms of side effects and efficacy. Quetiapine, lurasidone, and lithium stand out for their rapid effectiveness, whereas lamotrigine is preferred because its side effects are rare and it improves adherence. In choosing a drug, not only the severity of depression and clinical features but also clinical history will be decisive. For example, lithium may be prioritized for a patient with suicidal thoughts or prior suicide attempts, while lamotrigine may be a first choice for a woman with a mild depressive episode.

ÖD: The olanzapine–fluoxetine combination (OFC) is highlighted as an important option, especially for treatment-resistant cases and bipolar depression, and its effectiveness has been demonstrated in many studies. What is your view on its place in bipolar depression?

MÇE: I do not think the olanzapine–fluoxetine combination differs from combining olanzapine with another antidepressant. I suspect this combination emerged because both drugs are produced by the same company. Moreover, in comparative studies with OFC, there are either no data or very limited data for:
(1) comparisons of olanzapine combined with other antidepressants;
(2) comparisons with lithium plus antidepressant combinations;
(3) comparisons of other antipsychotics with fluoxetine or other antidepressants.
In this respect, there is insufficient scientific basis to favor OFC specifically; however, I may be able to state a more definitive view as clinical experience accumulates.

ÖD: In the treatment of bipolar depression, particularly in treatment-resistant cases, antidepressants are often used. Guidelines consider this approach reasonable, provided it is applied cautiously. Could you describe your clinical practice in this regard? In addition, are there any antidepressants regarded as safer with respect to the risk of a manic switch?

MÇE: The main limitation in choosing an antidepressant is their insufficient efficacy in bipolar depression and the potential for polypharmacy. The risk of a manic switch generally remains below 20%. Systematic reviews and meta-analyses indicate a tendency for agents with anticholinergic properties and broad receptor profiles to carry greater risk.

Prior to initiating an antidepressant in bipolar depression, I recommend carefully evaluating how previous manic episodes began, whether a recent manic episode has occurred, and whether mixed symptoms are present.

ÖD: In cases where bipolar depression is particularly severe, psychotic, catatonic, and/or treatment-resistant, electroconvulsive therapy (ECT) is an important option. Based on your clinical experience, which patient profiles benefit from ECT, and what criteria do you consider when deciding on this method? What are your views on seizure duration and session frequency?

MÇE: Unfortunately, there is no definitive way to know which patients will respond to ECT, but there are some clues. For example, there is evidence that it is more effective in melancholic depressions or in depressions where anhedonia is prominent. We also see it work in depressions with catatonia or severe psychomotor retardation. Seizure duration needs to be monitored by EEG, though this may not always be possible due to technical issues. A seizure duration of at least 20 seconds is required by EEG; if it is under 15 seconds, repeating the application within the same session is recommended. For severe patients, sessions can start three times per week and then be reduced to twice weekly. In severe malignant catatonia, the first three sessions are recommended on three consecutive days.

ÖD: Ketamine and esketamine have attracted attention in recent years with their rapid antidepressant effects. What are your thoughts on their role in bipolar depression?

On July 21, 2025, the U.S. Food and Drug Administration (FDA) convened an expert panel of renowned clinicians, researchers, and health policy makers to evaluate possible labeling changes regarding the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy. The panel addressed critical issues such as the role of the serotonin system in fetal development, the potential short- and long-term effects of SSRI exposure, and how to establish a risk–benefit balance in treating depression during pregnancy. The purpose of the panel was to review scientific evidence and to discuss the scope of current warnings in a way that would inform both clinicians and the public. However, many experts in perinatal psychiatry and obstetrics expressed concerns afterward, stating that while the panel emphasized risks, it did not sufficiently take into account the serious consequences of untreated depression and risked creating the impression of a one-sided presentation that could undermine scientific balance.

Key Points Highlighted in the Panel

Dr. Marty Makary, professor of surgery at Johns Hopkins University, emphasized that the risks of SSRI use in pregnancy should not be evaluated solely in relation to the medication but rather within a broader context that includes factors such as healthy lifestyle, community support, and natural light.
Dr. Anick Bérard, a pharmacoepidemiologist at the University of Montréal, pointed out that the use of paroxetine and fluoxetine has been associated with some adverse pregnancy outcomes, but argued that these risks must be assessed in absolute terms.
Dr. Jay Gingrich, a developmental neurobiologist from Columbia University, stated that SSRI exposure may alter emotional processing regions in the infant brain and therefore argued that warnings related to fetal brain development should be included on drug labels. Dr. Adam Urato, chief of maternal–fetal medicine at MetroWest Medical Center, noted that SSRI use could increase the risk of neurological problems emerging during adolescence in female children, calling for better public awareness.

Dr. David Healy, known for his critical work in psychopharmacology, argued that evidence for the effectiveness of SSRIs is weak even in severe depression and that discontinuation can lead to prolonged withdrawal syndromes.
Clinical psychologist Dr. Roger McFillin highlighted the limited efficacy and significant side effects of SSRIs, stressing the importance of lifestyle interventions and therapeutic methods.

Dr. Josef Witt-Doerring, a psychiatrist formerly with the FDA and founder of TaperClinic, noted that SSRI withdrawal symptoms are underestimated and that there are serious gaps in informing patients. Dr. Kay Roussos-Ross, who works in both obstetrics and psychiatry at the University of Florida, emphasized that untreated depression can lead to serious complications such as preeclampsia and preterm birth during pregnancy, and therefore SSRIs may be life-saving for some patients. Finally, Dr. Joanna Moncrieff from University College London argued that antidepressants have limited efficacy, that depression often resolves spontaneously, and that the risk–benefit balance must be carefully evaluated for each patient.

Reactions of the Experts After the Panel

The American College of Obstetricians and Gynecologists (ACOG) and the American Psychological Association (APA) stated that the panel highlighted risks while failing to sufficiently emphasize the well-documented harms of untreated depression. The Massachusetts General Hospital Center for Women’s Mental Health criticized the panel for having too few experts with direct experience in reproductive psychiatry. Perinatal psychiatrist Dr. Sunny Patel noted that the panel was presented in a way that could foster fear and misinformation among the public.
The National Center for Reproductive Psychiatry (NCRP) stated that current evidence does not show a direct causal relationship between prenatal SSRI exposure and congenital anomalies or autism spectrum disorders.

Conclusion

The use of SSRIs during pregnancy continues to be one of the controversial issues in modern psychiatry. The FDA panel held on July 21, 2025, brought the risk–benefit balance at the heart of this debate back into focus, highlighting both the critical role of the serotonin system in fetal development and the importance of contradictory findings regarding SSRI exposure. The views presented underscored the potential congenital and neurodevelopmental risks of SSRIs while also pointing out that the maternal and perinatal consequences of untreated depression cannot be ignored.
From a clinical perspective, SSRIs may be life-saving in some cases, whereas non-pharmacological approaches may be safer first-line options for mild or moderate depression. This underscores the need for treatment planning to be based on individual risk profiles, illness severity, stage of pregnancy,

What is GLP-1?

Glucagon-like peptide 1 (GLP-1) is an incretin hormone secreted throughout the gastrointestinal tract. It plays a vital role in glucose metabolism, satiety, and energy balance. Beyond its classical metabolic functions, increasing evidence highlights GLP-1’s central nervous system (CNS) activity, suggesting it may represent a promising target in treating addiction. Although the majority of the GLP-1 receptors (GLP-1Rs) are expressed in the gastrıintestinal system, various human tissues, including muscle, adipose tissue, bones, and numerous organs such as brain, express GLP-1Rs. These receptors mediate several physiological processes, including glucose homeostasis, gastric motility, lipid metabolism, and cardiovascular and neurologic functions.

Current Therapeutic Uses of GLP-1 Receptor Agonists (GLP-1RAs)

The therapeutic potential of GLP-1 receptor agonists (GLP-1RAs) has been well established in type 2 diabetes, cardiovascular disease, and obesity. Currently approved GLP-1RAs include albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide. Notably, newer agents like semaglutide have gained attention due to their pronounced effects on weight reduction, even among individuals without diabetes.

The Role of GLP-1in Brain

Importantly, GLP-1 and its analogs can cross the blood-brain barrier and are also endogenously synthesized in specific brain regions, including the hypothalamic nuclei, nucleus tractus solitarius (NTS), and caudal brainstem.

In the central nervous system, GLP-1 has been shown to influence mitochondrial function, synaptic plasticity, and neuroinflammatory pathways, thereby exerting neuroprotective effects. These mechanisms have prompted investigation into GLP-1RAs for neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.

GLP-1 and Addiction

Crucially, recent preclinical and clinical evidence suggests that GLP-1 also modulates the mesolimbic reward system, which is central to the neurobiology of addiction. GLP-1Rs in the VTA and nucleus accumbens influence dopamine-mediated behaviors associated with reward, craving, and reinforcement. Activation of these receptors has been found to attenuate behaviors induced by addictive substances, including alcohol, nicotine, opioids, cocaine, and amphetamines. Animal studies have demonstrated that GLP-1RA administration can reduce alcohol intake, blunt drug-seeking behaviors, and alleviate withdrawal symptoms. These effects appear to stem from both hypothalamic appetite-regulating circuits and direct projections from NTS GLP-1 neurons to mesolimbic regions. Taken together, the accumulating evidence positions GLP-1R agonists as potential therapeutic agents in the management of substance use disorders.

The Global Burden and Treatment Challenges of Depression

According to the World Health Organization, the global prevalence of depression in 2015 was reported to be 4.4%. In other words, approximately one in every 20 people worldwide is diagnosed with depression at some point in their life. Although psychotherapies and selective serotonin reuptake inhibitors (SSRIs) are available as first-line treatments for patients, the limitations of conventional methods used to manage depression pose significant challenges. SSRIs typically require about two to six weeks to become effective, and early side effects may paradoxically lead to feelings of agitation, anxiety, and apathy. Despite SSRI/SNRI treatment, the average remission rate is around 30–40%. Moreover, nearly one-third of patients with depression are treatment-resistant, meaning they do not respond to two different treatment strategies. However, new developments offer a promising outlook; one of these is the use of esketamine, a novel NMDA receptor antagonist, for individuals experiencing treatment-resistant depression.

Pharmacological Properties and Clinical Effects of Esketamine

Esketamine is the S-enantiomer of the racemic mixture of ketamine. In patients with depression, dysfunctional and overactive N-methyl-D-aspartate (NMDA) receptors may lead to reduced neuroplasticity. Ketamine works by blocking these receptors, which enhances glutamate release and signal transmission, thereby resulting in improvements in mood and behavior.Esketamine (S-ketamine) is twice as potent as ketamine and has a higher affinity for NMDA receptors, providing a much stronger and faster analgesic effect.

Safety, Side Effects and Clinical Application

A recent study published in the International Journal of Neuropharmacology reported that esketamine monotherapy was statistically effective compared to a placebo-controlled group. Positive changes were observed within 24 hours after the first dose and persisted for up to one month throughout the treatment period. In the study’s long-term safety and efficacy extension focusing on prolonged use, researchers found no evidence of cognitive decline associated with continued administration. The response was relatively maintained over time, with only 5.3% of participants withdrawing from the study due to esketamine being reported as ineffective. In some participants, symptom scores continued to improve progressively. Nausea, dissociation, and dizziness are among the most commonly reported side effects by participants using esketamine.
Increases in blood pressure peak approximately 40 minutes after esketamine administration and persist for around four hours. Esketamine, at all currently recommended doses, causes elevations in systolic and/or diastolic blood pressure. Real-world studies

Brexpiprazole’s long elimination half-life of 91 hours allows once-daily dosing, improving adherence. Food intake does not affect absorption. Peak plasma levels are reached approximately 4 hours after dosing, with steady-state concentrations achieved by days 10–12.
Oral bioavailability of brexpiprazole is high (95%), with approximately 99% binding to plasma proteins. Brexpiprazole is primarily metabolized via the CYP3A4 and CYP2D6 enzymes. Clinically significant drug interactions are rare; however, when co-administered with a CYP3A4 inhibitor, the dose should be reduced by half, while concomitant use with a CYP3A4 inducer requires doubling the dose (up to a maximum of 12 mg/day), preferably administered in divided doses.

What Can Be Done If Brexpiprazole Treatment Is Insufficent?

In cases where brexpiprazole treatment is insufficient, switching to another atypical antipsychotic or considering combination therapy may be appropriate. The use of other atypical antipsychotics such as risperidone, olanzapine, and quetiapine is particularly common. Increasing the dose beyond established therapeutic limits has not proven effective and is therefore not recommended. As an adjunctive strategy, augmentation with agents such as valproate, lamotrigine, lithium, or benzodiazepines may also be considered.

Comparison with Aripiprazole

Brexpiprazole shows higher affinity for dopamine D1, D2, and D4 receptors, but lower affinity for D3 receptors compared with aripiprazole. It also exerts stronger antagonism at 5-HT2A receptors. These properties are associated with a lower risk of akathisia and insomnia, and a less activating profile. Its lower intrinsic activity may further reduce activation-related side effects. Stronger 5-HT1A partial agonism may explain more prominent antidepressant and anxiolytic effects.

Discussion and Conclusion

Brexpiprazole represents an important treatment alternative in adults owing to its efficacy and generally favorable tolerability. Its side-effect profile and long half-life may provide particular advantages in treatment-resistant cases. Although not yet approved for use in children and adolescents, brexpiprazole has been reported to have a side-effect profile similar to that observed in adults, with lower rates of sedation and metabolic adverse effects. When used as an adjunct to antidepressant therapy, brexpiprazole has demonstrated potential benefits in improving mood, anxiety, and agitation symptoms. Nevertheless, larger and more rigorously designed studies are required to determine the generalizability of these findings.

The Number Needed to Treat (NNT) is an important metric used in clinical research and evidence-based medicine to evaluate treatment efficacy. It represents the average number of patients who need to receive an intervention for one additional patient to benefit, compared with a control group (typically placebo or standard treatment). In simpler terms, it indicates how many patients must be treated for one person to experience a beneficial effect. Mathematically, it is the inverse of the Absolute Risk Reduction (ARR):

*CER (Control Event Rate): The incidence of the event in the control group (the untreated or placebo group)
**EER (Experimental Event Rate): The incidence of the event in the experiment group (the group receiving the drug or treatment)

For example, considering escitalopram, if the response rate in the placebo group is 35%, and in the escitalopram group it is 55%, the Absolute Risk Reduction (ARR) can be calculated as follows:

ARR=0,55−0,35=0,20
-> NNT=1/ARR 1/0,20=5

This result indicates that, for every five patients treated with escitalopram, one patient experiences an additional clinical benefit compared to placebo. In other words, when five patients receive the treatment, only one of them shows a significant improvement that can be attributed to the drug itself.

The Balance Between NNT and NNH

While evaluating the benefits of a treatment, it is also important to consider the Number Needed to Harm (NNH) alongside the NNT.