International Journal of Neuropsychopharmacology

Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report Significance Statement Patients with markedly treatment-resistant major depression have a low likelihood of benefiting from antidepressant treatments and a

• Early meaningful improvement often progressed to full response (mood, functioning, QoL)

📌 New Clinical avenue

These data support VNS as a durable intervention that expands therapeutic options for treatment-resistant depression.

Check the paper for more information: doi.org/10.1093/ijnp...

Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report Significance Statement Patients with markedly treatment-resistant major depression have a low likelihood of benefiting from antidepressant treatments and a

>80% of patients with clinically meaningful improvement at 12 months maintained benefit at 18 and 24 months• Low rates of loss of response over time

• Delayed response observed: up to ~38% of patients without benefit at 12 months improved during the second year

Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report Significance Statement Patients with markedly treatment-resistant major depression have a low likelihood of benefiting from antidepressant treatments and a

🧠 Neurostimulation is redefining long-term treatment in psychiatry
Vagus nerve stimulation (VNS) & sustained benefit in depression
📄 A recent paper published in IJNP reports robust long-term outcomes with VNS in MDD!
📊 Impressive findings:

Modulatory effects of GLT-1 enhancer, MC-100093, on glutamate uptake and associated signaling pathways in female and male alcohol preferring rats exposed to ethanol Significance Statement This study reports the preclinical testing of novel drug, MC-100093, for the attenuation of ethanol intake. The pharmacological aspe

🧠 Targeting glutamate uptake pathways
By restoring glutamate homeostasis in a reward-relevant brain region, MC-100093 highlights a target-focused, mechanism-driven strategy for AUD pharmacotherapy.

👉 Read more on: doi.org/10.1093/ijnp...
#DrugDiscovery #Pharmacology #CNSDrugs #AlcoholUseDisorder

🔬 Pharmacodynamic and mechanism-of-action insights
MC-100093 demonstrated functional modulation of glutamatergic targets, normalizing ethanol-induced alterations within the nucleus accumbens:
- GLT-1 & xCT,
- NF-κB & p-Akt signalling

💊 Preclinical pharmacology with implications for AUD drug development

This study reports the preclinical evaluation of MC-100093, a novel compound that reduces voluntary ethanol intake in both male and female rats, supporting its potential as a pharmacological lead for alcohol use disorder.

Current and novel dual orexin receptor antagonists for the treatment of insomnia: the emergence of vornorexant Abstract. Insomnia is a serious public health concern. As the widely prescribed hypnotics that positively modulate gamma-aminobutyric acid (GABA)A receptor

Clinical Perspective: While offering clear mechanistic and safety advantages, the optimization of DORAs continues to evolve around pharmacokinetics and next-day tolerability.
Check more here: doi.org/10.1093/ijnp...
#SleepMedicine #Neuropharmacology #Insomnia #Orexin #DORA #Neurology #Psychiatry

Current and novel dual orexin receptor antagonists for the treatment of insomnia: the emergence of vornorexant Abstract. Insomnia is a serious public health concern. As the widely prescribed hypnotics that positively modulate gamma-aminobutyric acid (GABA)A receptor

Clinical Distinctions of DORAs:
✅ Preserved sleep architecture: Increase both NREM and REM sleep.
✅ No dependency signal: Long-term use studies show no evidence of tolerance, physical dependence, or rebound insomnia.
✅ Sustained efficacy: Demonstrated in both acute and long-term treatment.

Current and novel dual orexin receptor antagonists for the treatment of insomnia: the emergence of vornorexant Abstract. Insomnia is a serious public health concern. As the widely prescribed hypnotics that positively modulate gamma-aminobutyric acid (GABA)A receptor

The Orexin System: Understanding the Modern Insomnia Treatment

By pharmacologically targeting dual orexin receptor antagonists (DORAs), this class of agents promotes sleep through a fundamentally different mechanism

DORAs ⬇️ the "wake drive" rather than inducing widespread neuronal inhibition

As the year draws to a close, we wish you and your loved ones a very Happy Holiday season and a peaceful, healthy, and productive New Year.

We look forward to the continued collaboration of the IJNP community in 2026.

On behalf of the IJNP Editorial Management Group

Individual differences in dopamine-related traits influence mood effects of dopamine D2-antagonist and antidepressant treatment expectations AbstractBackground. High trait anhedonia and low trait extraversion have both been previously related to not only low state positive affect but also depres

Read more on: doi.org/10.1093/ijnp...

Individual differences in dopamine-related traits influence mood effects of dopamine D2-antagonist and antidepressant treatment expectations AbstractBackground. High trait anhedonia and low trait extraversion have both been previously related to not only low state positive affect but also depres

The bottom line: This U-shaped model moves us from trial-and-error toward precision.
✔️Prioritizing DA strategies for low-positive-affect depression.
✔️Exercising extreme caution with DA stimulation in high-trait patients.
✔️Using trait assessment to guide both pharmacological and placebo treatment

➡️For individuals with low positive affectivity, a dopamine precursor increased state positive affect.
➡️For individuals with high positive affectivity, the same intervention reduced state positive affect.

#dopamine #precisionpsychiatry #mood #bipolar #depression #neuropsychopharmacology

Dopamine's link to positive affect isn't linear—it could be U-shaped🧠

The recently published paper in IJNP shows that an individual's trait positive affectivity critically moderates how dopamine modulation influences state positive affect.

In a double-blind design:

🧠 Our brain circuits were shaped under these conditions, and some of the most ancient pathways remain deeply conserved across vertebrate species.
This recent review highlights a fascinating framework: looking beyond mammals and exploring alternative models for studying human mental disorders.

Connect with the international community of neuropsychopharmacology!

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Using pooled data from three Phase 3 trials, the authors show that adjunctive brexpiprazole provides meaningful symptom relief in both minimally responsive and partially responsive patients.
Check the paper for more: doi.org/10.1093/ijnp...

Editor’s Pick of the month!
This month’s featured paper delivers important insights for the large group of patients with major depressive disorder who achieve only limited improvement on standard antidepressants.

They suggest that future research should directly compare oral and depot naltrexone, systematically assess blinding, and account for comorbidities and sex differences to clarify ketamine’s mechanisms of action and guide clinical practice

Check the paper for + info: doi.org/10.1093/ijnp...

A recent commentary by @igorbandeira.bsky.social et al. highlights the steps in clinical trial design that combine ketamine and naltrexone for major depression, allowing for a mechanistic approach.

@stanfordpsy.bsky.social
#depression #opiod #ketamine #resistantdepression #clinicaltrials

Opioid and Ketamine in the clinic: key methodological considerations

The question of whether ketamine’s antidepressant effects are mediated by glutamatergic plasticity or opioid receptor signalling remains a subject of considerable debate.

Partial agonist antipsychotic drugs differentially interact with a secondary binding site at the dopamine D2 receptor Highlights - Aripiprazole and brexpiprazole showed significantly increased dissociation from the dopamine D2 receptor upon L94A mutation, indicating that t

💊 Distinct D₂R binding poses may produce clinically meaningful differences in efficacy, onset, and tolerability

📄 Read the full study here: doi.org/10.1093/ijnp...

Partial agonist antipsychotic drugs differentially interact with a secondary binding site at the dopamine D2 receptor Highlights - Aripiprazole and brexpiprazole showed significantly increased dissociation from the dopamine D2 receptor upon L94A mutation, indicating that t

⚙️ Mechanistic insight:
Aripiprazole / brexpiprazole → SBP-dependent binding
→ May help stabilize dopaminergic tone and reduce extrapyramidal side effects.

Cariprazine / lumateperone → canonical D₂R binding, faster dynamics
→ Could underlie different temporal or regional dopamine modulation.

🧩 In this study, 4 clinically approved D₂R partial agonists (DPAs) were tested for how they interact w/ a secondary binding pocket (SBP) in the receptor

🔬 Key finding:
Mutating a residue in the SBP(L94A) accelerated dissociation of aripiprazole and brexpiprazole, but not cariprazine or lumateperone

🧠 Do dopamine D₂ partial agonists all bind the same way? Maybe not.
New evidence challenges the idea that all “third-generation” antipsychotics share a single D₂ receptor binding mode.

#Neuropsychopharmacology #Antipsychotics #Dopamine

Sex-specific prolactin disturbance and divergent gonadal hormone correlates in first-episode schizophrenia AbstractBackground. Hyperprolactinemia and altered prolactin (PRL) levels are well-documented in schizophrenia. However, very few studies have investigated

Given prolactin’s roles in mood, stress, sexual health, and bone metabolism, early endocrine assessment could inform sex-specific care in schizophrenia.

🔗 Read +: doi.org/10.1093/ijnp...
#Schizophrenia #Endocrinology #Psychiatry #FirstEpisodePsychosis #Neuroendocrinology

📊 Abnormal PRL levels were nearly 4× more frequent in males than in females.
📊 HyperPRL patients also showed higher testosterone and FSH

These findings suggest that PRL–gonadal hormone dysregulation may be intrinsic to psychosis onset, not only drug-induced.

🧠 Hyperprolactinemia is usually seen as a side effect of antipsychotics — but could it be part of schizophrenia itself?
In first-episode, non- to minimally treated patients, there was a clear sex-specific endocrine disturbance.

Mechanism of the AMPK/SIRT1 pathway in gut dysbiosis–mediated postoperative cognitive dysfunction in aged mice AbstractObjective. Postoperative cognitive dysfunction (POCD) is a prevalent complication in older patients who undergo surgery that requires anesthesia. T

🧩 Read more: doi.org/10.1093/ijnp...

#Neuroscience #Microbiome #BrainHealth #Surgery #Aging #Nutraceutical

🔥In aged mice, gut dysbiosis worsened POCD by increasing brain inflammation.

💊Treatment with the probiotic VSL#3 restored healthy gut bacteria, reduced neuroinflammation, and improved memory via the AMPK/SIRT1 pathway, a key regulator of energy balance and inflammation ⚡