Arketamine, a new rapid-acting antidepressant: A historical review and future directions

The extracted text presents a narrative, historical review rather than a systematic meta-analysis; the paper compiles and interprets findings from preclinical experiments, receptor binding studies, imaging and molecular biology work, and limited clinical reports. The authors draw on animal models of depression (including chronic social defeat stress and lipopolysaccharide models), in vitro studies using microglial and neuronal cell lines, receptor profiling panels, functional MRI data in animals, RNA sequencing of prefrontal cortex tissue, and selected human studies (an open‑label arketamine infusion trial and prior clinical ketamine/esketamine trials). The extracted text does not report a formal methods section for literature searching: there is no description of databases searched, search dates, inclusion/exclusion criteria, or formal risk‑of‑bias assessment. Instead, the review organises evidence by theme (history; human clinical comparisons; animal and monkey studies; receptor and intracellular signalling mechanisms) and integrates mechanistic findings from biochemical, pharmacokinetic and genetic manipulation experiments reported in the primary studies cited by the authors. Important experimental details cited in the text include receptor affinity (Ki) values, single‑dose IV infusion regimens reported in clinical case series (0.5 mg/kg), and the use of pharmacological inhibitors and molecular tools such as siRNA and heteroduplex oligonucleotides in mechanistic rodent and cell experiments.

Comparative pharmacology and clinical signals: The racemic (R,S)-ketamine has a reported NMDAR Ki of 0.53 μM; esketamine has higher affinity (Ki = 0.30 μM) while arketamine has lower affinity (Ki = 1.4 μM). Despite lower NMDAR affinity, multiple preclinical studies found that arketamine produced more potent and longer‑lasting antidepressant‑like effects than esketamine in rodent models. Arketamine also showed fewer psychotomimetic and dissociative side effects in animals and, where reported, in humans. Clinically, esketamine nasal spray received regulatory approval in 2019 for treatment‑resistant depression, but concerns about efficacy and safety remain. A first open‑label clinical study of arketamine (single IV infusion of 0.5 mg/kg) reported rapid and sustained antidepressant effects in treatment‑resistant MDD with low acute psychotomimetic and dissociative symptoms; a Phase 2 randomised trial is noted as underway. Mechanistic findings challenging an exclusive NMDAR hypothesis: Several lines of evidence presented suggest that NMDAR blockade alone does not account for arketamine’s antidepressant‑like actions. A highly potent selective NMDAR antagonist ((+)-MK-801, Ki = 0.0019 μM) did not produce antidepressant effects in patients despite showing effects in some rodent models. Functional MRI data in rats indicated that arketamine produced different regional responses compared with esketamine and racemic ketamine, arguing against simple NMDAR inhibition as the sole driver. Pharmacokinetic profiles of the two enantiomers were reported as similar, further weakening a pharmacokinetic explanation for efficacy differences. ERK — NRBP1 — CREB — BDNF signalling in microglia: Convergent preclinical data implicate an ERK‑CREB‑BDNF cascade, particularly in microglia, as central to arketamine’s sustained effects. Arketamine increased NRBP1 expression and the phospho‑CREB/CREB ratio in primary microglia and in medial prefrontal cortex (mPFC) tissue; NRBP1 and CREB were shown to physically interact. ERK inhibition (SL327) attenuated arketamine‑induced increases in NRBP1, phospho‑ERK/ERK, phospho‑CREB/CREB and BDNF in microglia. Gene‑silencing approaches targeting CREB or the CREB‑binding sequences of BDNF exon IV reduced arketamine’s behavioural antidepressant‑like effects and the associated molecular changes. Mannosylated clodronate liposomes, which perturb microglial phenotype, also attenuated arketamine’s antidepressant‑like effects and blunted increases in BDNF and anti‑inflammatory microglial markers. TGF‑β1 and microglia: RNA sequencing in the prefrontal cortex identified Tgfb1 as differentially expressed between enantiomer treatments. The authors report that microglial TGF‑β1 contributes to arketamine’s effects: partial microglial depletion with a CSF‑1 receptor inhibitor blocked arketamine’s antidepressant‑like actions in CSDS mice. Intranasal TGF‑β1 produced rapid and sustained antidepressant effects in the CSDS model, and these effects were blocked by TrkB inhibition (ANA‑12), suggesting an interaction between TGF‑β1 signalling and BDNF‑TrkB pathways. Other receptor and channel findings: A 98‑target receptor/enzyme screen at 10 μM identified the PCP‑binding site of NMDAR for both enantiomers and mu‑opioid receptor as a hit for esketamine but not for arketamine. Clinical data on opioid involvement are mixed: one small human study reported that naloxone blocked (R,S)-ketamine’s antidepressant and anti‑suicidal effects, whereas animal studies often found no naloxone effect. Arketamine shows greater affinity for sigma‑1 receptors (Ki = 27 μM) than esketamine (Ki = 500 μM), but the authors judge sigma‑1 receptors unlikely to explain rapid antidepressant action because other sigma‑1‑affine antidepressants do not reproduce ketamine‑like rapidity. KCNQ2 (a voltage‑gated potassium channel subunit) has emerged as another candidate regulator of sustained antidepressant responses, and a KCNQ activator (retigabine/ezogabine) showed antidepressant effects in a clinical trial, suggesting possible combinatory strategies. Safety and broader therapeutic potential: Preclinical and limited clinical data indicate that arketamine produces fewer acute psychotomimetic and dissociative effects and has lower apparent abuse liability than (R,S)-ketamine or esketamine. The review also collates reports of arketamine’s beneficial effects in animal models of neurological disorders (Parkinson’s disease, multiple sclerosis) and notes non‑psychiatric properties of ketamine enantiomers including anti‑inflammatory and neuroprotective effects. Ongoing clinical development by multiple companies is listed, but randomised controlled trials directly comparing enantiomers are lacking.

Zhang and colleagues interpret the assembled evidence to propose that arketamine is a promising candidate for a rapid‑acting antidepressant with a preferable side‑effect profile compared with racemic ketamine and esketamine. They emphasise that the antidepressant‑like efficacy of arketamine in preclinical models appears dissociated from simple NMDAR blockade and instead implicates intracellular signalling cascades in microglia, notably ERK activation leading to CREB phosphorylation, NRBP1 involvement and subsequent BDNF upregulation that may act via TrkB on neurons to restore synaptic structure. The authors position these findings relative to earlier research by noting that while NMDAR antagonism was initially considered central to ketamine’s effects, non‑ketamine NMDAR antagonists did not recapitulate clinical antidepressant responses and some mechanistic data (fMRI, pharmacology) argue against NMDAR inhibition as the dominant pathway for arketamine. They also discuss conflicting data on opioid receptor involvement, concluding that opioid signalling is unlikely to be a major mechanism for ketamine’s antidepressant actions given mixed clinical and preclinical results and receptor profiling data. Key limitations acknowledged include the paucity of randomised clinical data on arketamine (the published human evidence is an open‑label pilot), incomplete understanding of the precise molecular and cellular mechanisms, and translational uncertainty between animal models and patients. The authors call for head‑to‑head randomised trials comparing arketamine and esketamine, further mechanistic studies including exploration of brain‑body communication (gut‑microbiota‑brain and brain‑spleen axes), and investigation of arketamine’s potential benefits in neurological and inflammatory disorders. They also note the need to clarify whether classical psychedelics share overlapping molecular mechanisms with arketamine.

The review concludes that arketamine may represent a new rapid‑acting antidepressant candidate with fewer acute side effects than (R,S)-ketamine and esketamine, supported by convergent preclinical evidence and a preliminary open‑label human study. Clinical development programmes are in progress, and the authors anticipate randomised trials will clarify clinical efficacy and safety. Future work should resolve the detailed molecular and cellular mechanisms—particularly the role of microglial ERK‑CREB‑BDNF and TGF‑β1 signalling—and assess broader therapeutic applications in neurological and inflammatory conditions.