TAP Psychopharmacology Bulletin - New Horizons / 2025 July

One of the most common challenges encountered in clinical psychiatric practice is weight gain associated with psychotropic medications and the subsequent complications arising as a result of it. These complications are not only limited to changes in physical appearance and also encompass significant health risks to the patient.
Although various pharmacological and non-pharmacological strategies have been employed to manage weight gain, this issue remains prevalent and cannot be overlooked by psychiatric services. Novel treatments for obesity offer promising alternatives, particularly for overweight individuals and patients experiencing drug-induced weight gain.
As with any pharmacological intervention, the benefit-risk profile of these treatments must be carefully evaluated. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, recently emerged as a treatment option for obesity. It exerts its effects primarily by delaying gastric emptying. Nevertheless, potential drug interactions and clinical outcomes associated with semaglutide are not fully elucidated yet. Consequently, sharing clinical experiences from real-world settings is critical in guiding other clinicians.

Development of lithium toxicity in a patient who had been using oral lithium at a stable dose of 1200 mg/day for 14 months with therapeutic serum levels and no signs of toxicity. Following the initiation of semaglutide treatment, the patient's serum lithium level increased from 0.9 mEq/L to 2.4 mEq/L, despite no change in the lithium dosage. The lithium level returned to normal with intravenous hydration, and the therapeutic serum level was subsequently maintained with a reduced lithium dose of 600 mg/day.
GLP-1 receptor agonists enhance insulin secretion while suppressing glucagon and delaying gastric emptying in a dose-dependent manner. This delayed gastric transit may interfere with the absorption and distribution of concurrently administered oral medications. In conclusion, while new pharmacological agents such as semaglutide hold promise in the treatment of conditions like obesity, clinicians must remain vigilant regarding possible interactions with ongoing psychotropic regimens. Careful monitoring and individualized assessment are essential to ensure safe and effective treatment outcomes.

M.D. Furkan Yazıcı
DOI: 10.1097/JCP.0000000000002017
DOI: 10.1007/5584_2020_496

Does AI Outperform Psychiatrists in Tardive Dyskinesia Screening?

One of the major complications associated with the long-term use of antipsychotic medications in clinical practice is tardive dyskinesia (TD). However, TD is often overlooked or diagnosed late. In the United States, this motor disorder affects approximately 2.6 million individuals, yet only about 40,000 patients receive treatment. Early diagnosis plays a crucial role in preventing the progression of this condition. Although there are approved treatments for TD such as valbenazine and tetrabenazine,

Cariprazine stands apart pharmacodynamically due to its strong affinity not only for D2 receptors—similar to BRX—but also for D3 receptors. It exhibits approximately 40% intrinsic activity at D2Rs and up to 60% at D3Rs. At a daily dose of 3 mg, CAR binds ~92% of D2Rs and ~79% of D3Rs. Notably, CAR may offer benefits for primary negative symptoms in schizophrenia, likely due to its high D3 affinity. D3 autoreceptor blockade in the ventral tegmental area may enhance dopamine release in the prefrontal cortex, which could improve negative symptoms and contribute to its antidepressant effects. Consequently, CAR is the only dopamine partial agonist approved for bipolar depression (NNT = 4–10).

Comparative Clinical Efficacy

All three agents share partial 5- HT1A agonist, 5-HT2A antagonist, and partial D2 agonist properties, which are believed to augment antidepressant effects in major depressive disorder (MDD).

Estimated NNT values are as follows: ARI = 9, BRX = 12–16, CAR = 9–16. The antidepressant effect of CAR is thought to benefit from its D3R partial agonism and full 5-HT1A agonist activity.

All three drugs are effective in the treatment of acute schizophrenia. Comparative efficacy data suggest similar outcomes with NNTs as follows: ARI = 8, BRX = 7, CAR = 10. For relapse prevention during maintenance therapy, NNT values are reported to be between 4 and 5 for all three agents.

Pharmacokinetics, Drug Interactions, and Metabolism

Pharmacokinetic profiles differ considerably among the three agents. ARI has a half-life of approximately 75 hours, and with its active metabolite, dehydro-aripiprazole, total elimination may extend to 86 hours. BRX has a half-life of approximately 94 hours and lacks a major active metabolite. CAR, on the other hand, has a variable half-life of 2–4 days, with active metabolites that may take 1–3 weeks for full elimination. This extended profile may delay steady-state levels, leading some clinicians to prematurely increase doses due to a perceived lack of early efficacy. Nevertheless, the long half-life and active metabolites provide a buffer against missed doses —an advantage in clinical practice.
All three drugs are primarily metabolized via CYP2D6 and CYP1A2.

Introduction

The long-term use of antipsychotics in the treatment of schizophrenia has been a subject of ongoing debate for years. One key point of discussion is whether sustained dopamine D2 receptor blockade remains effective over time. A study published in 2025 by Tiihonen et al. in the American Journal of Psychiatry, focused specifically on first-episode schizophrenia patients who were maintained under continuous D2 blockade and followed for up to 10 years to assess relapse rates.

Study Design and Methodology

Using Finland's national health registry, individuals under the age of 45 who were hospitalized with a firsttime diagnosis of schizophrenia between 1996 and 2014 were screened. A total of 4,788 patients with no prior antipsychotic exposure were included in the study. Of these, 305 patients received long-acting injectable (LAI) antipsychotics within 30 days of diagnosis, forming the “continuous treatment” group. The remaining patients, who were either untreated, intermittently treated, or received oral antipsychotics, constituted the “other” group. The primary outcome was defined as hospitalization due to psychotic relapse, with a follow-up duration of 10 years.

Results – Relapse Rates and Trends

In the LAI group (n = 305), a 45% relapse rate was observed over 10 years, corresponding to a 55% relapse-free rate. The annual relapse rate per person-year was 26% in the first year, which declined to 5% by year five. From the sixth year onward, only four relapses occurred, reflecting a 3% annual relapse rate. Relapse rates decreased significantly with continued treatment. In contrast, the “other” treatment group had a 55% relapse rate over 10 years.

Response to the Dopamine Supersensitivity Hypothesis

The dopamine supersensitivity hypothesis posits that prolonged D2 blockade may sensitize dopamine receptors, potentially leading to treatment-resistant psychotic episodes over time.

However, this study found the opposite trend: as treatment duration increased, relapse rates decreased, no dose escalation was needed, and in fact, median DDD (defined daily dose) declined from 1.20 to 1.04 over the 10-year period.

Postpartum depression (PPD) affects approximately 10–15% of women and is characterized by significant mood symptoms and functional impairment. The therapeutic effects of traditional antidepressants typically emerge within 2–4 weeks. However, in the context of PPD— particularly regarding early intervention and mother-infant bonding—faster-acting agents are needed. Neurosteroid-based treatments have garnered increasing attention in this regard. Brexanolone, a GABA-A receptor modulator, along with its oral alternatives, have begun to reshape the treatment paradigm in recent years.

IV Brexanolone: The First and Only Approved Intravenous Treatment

Brexanolone (Zulresso®) is the intravenous formulation of allopregnanolone. In 2019, it became the first FDA-approved medication specifically indicated for the treatment of PPD. Its mechanism of action involves positive allosteric modulation of GABA-A receptors, resulting in a rapid and robust therapeutic effect.

In Phase III clinical trials, a meaningful clinical response was observed within 12–24 hours following a 60-hour infusion, with sustained effects lasting up to 30 days. However, due to potential adverse effects such as sedation, confusion, and in rare cases, syncope, brexanolone treatment is restricted to certified healthcare facilities under the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program.

Zuranolone: Rapid Onset with Oral Administration

Zuranolone became the first FDAapproved oral neurosteroid for PPD in 2023. It is administered as a oncedaily 50 mg dose over a 14-day course and acts by modulating GABA-A receptors. By enhancing the effect of GABA, zuranolone exerts rapid anxiolytic and moodstabilizing effects within a few days. Since its mechanism does not directly involve the serotonin or dopamine systems, it presents a lower risk of drug interactions and a shorter duration of action.

A Non-Monoaminergic Pathway: New Antidepressants Targeting GABA

As an alternative to the slow-acting, serotonin-based mechanisms of traditional antidepressants, neurosteroids are opening a completely new therapeutic door: the GABA-A receptor system. Following childbirth, endogenous allopregnanolone levels drop, resulting in a form of "silencing" within the GABA-A system. This disruption is increasingly recognized as a key contributor to prominent postpartum depression symptoms such as anxiety, irritability, and insomnia. By positively modulating GABA-A receptors, zuranolone and brexanolone restore GABAergic tone and alleviate symptoms.