Recent advances in the synthesis of antidepressant derivatives: pharmacologic insights for mood disorders

Abstract

Mood disorders, including depression, remain a significant global health concern, necessitating continuous efforts to develop novel and more effective antidepressant therapies. Although there have been significant advancements in comprehending the biology of Major Depressive Disorder (MDD), a considerable number of people suffering from depression do not exhibit positive responses to the pharmacologic treatments now available. This study specifically examines emerging targets and potential future approaches for pharmaceutical interventions in the treatment of MDD. The discussion revolves around novel therapeutic agents and their effectiveness in treating depression. The focus is on the specific pathophysiological pathways targeted by these agents and the amount of evidence supporting their use. While conventional antidepressants are anticipated to continue being the primary treatment for MDD in the foreseeable future, there is currently extensive research being conducted on numerous new compounds to determine their effectiveness in treating MDD. Many of these compounds have shown encouraging results. This review highlighted the recent advances in the synthesis of antidepressant derivatives and explores their pharmacologic insights for the treatment of mood disorders.

Introduction

Depression is a significant mood disease characterized by a continuous sense of sadness, severe low mood, impaired thinking, hopelessness, and lack of interest. Major depressive disorder (MDD) is a significant public health issue that causes substantial impairment in occupational, psychologic, and social functioning (Kupferberg et al. 2023). Over time, it may also encompass incapacity to feel pleasure, impairment in motor function, alterations in sleep and eating patterns, trouble in focusing, and contemplation of suicide (Clack 2019). Depression is classified as one of a diverse set of illnesses, which are broadly categorized in the International Classification of Diseases (ICD) issued by the World Health Organization (WHO). The current version of the ICD-11 categorizes depressive disorders into several types: single episode depressive disorder and recurrent depressive disorder. In addition, there are various other types of depression, including anxiety and mixed depressive disorder, other defined depressive disorders, dysthymic disorder (persistent depressive disorder), and nonspecific depression (Reed et al. 2019).

The etiology of this sickness remains elusive, and it was not until the mid-1960s that a molecular rationale for the condition gained acceptance (Fig. 1). The monoamine theory, which is widely recognized, posits that depression is caused by a lack of brain monoamine activity, namely noradrenaline (NA) and/or serotonin (5-HT) (Hindmarch et al. 2002). According to this idea, one way to cure depression is to increase this monoaminergic activity. In a typical brain, neurotransmitters such as NA or 5-HT are released into the synapse by the presynaptic neuron (Elhwvegi et al. 2004).

Fig. 1.

Main mechanism of depression where the primary anatomical components which encompasses the amygdala and the hippocampus

Given that it influences neurogenesis and synaptic plasticity, vascular endothelial growth factor may also have a role in the pathophysiology of depression (Fournier and Duman 2012). Several inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), IL-6, and interleukin 1-β (IL-1β), stop the growth of neurons, especially in the hippocampal region (Monje et al. 2003; Iosif et al. 2006; Raison et al. 2006). Anlar et al. (1999) reported that specific regions of the brain produce insulin-like growth factor 1, which plays a significant role in neurogenesis and cell differentiation. The neurotransmitter gamma-aminobutyric acid (GABA), the dopaminergic and glutamatergic systems, the hypothalamus–pituitary–adrenal (HPA) axis, brain-derived neurotrophic factor (BDNF), and its intracellular signaling pathways are other factors involved in the pathophysiology of depression. Figure 2 shows two pharmacophores that are linked together to generate new molecular templates as anti-depressants agents. Recent research suggests that these factors may contribute to a delayed response to antidepressant therapy (Palazidou 2012).

Fig. 2.

General structure of proposed scaffold as antidepressant agents

During the synapse, the neurotransmitter has the ability to interact with the postsynaptic neuron to provide its intended action. Alternatively, it can undergo metabolism or be taken back up by the presynaptic neuron. In addition, within the synapse, the neurotransmitter has the ability to engage with certain receptors located in the presynaptic neuron, referred to as autoreceptors, which suppress its activity (Kennedy et al. 2013). Thus, potential strategies for enhancing the monamine level in the brain could include as follows: (Celada et al. 2004).

• To inhibit the presynaptic autoreceptors, particularly the α2-adrenoceptors (α2-AR), and some 5-HT subtype receptors (1A or 1B);

• To inhibit the re-uptake of monoamine neurotransmitters such as NA or 5-HT at the synapse, using selective norepinephrine re-uptake inhibitors (SNRIs), selective serotonin re-uptake inhibitors (SSRIs), or norepinephrine re-uptake inhibitors;

• To suppress the metabolic pathways (monoamine oxidase inhibitors, MAOIs);

• To directly influence the activity of neurons that produce monoamines.

An effective remedy for this difficulty arose in the early 21st Century with the discovery of ketamine, a glutamatergic drug, which demonstrated rapid and long-lasting antidepressant effects (Berman et al. 2000). Extensive data has been accumulated, demonstrating the potential of glutamatergic medicines, such as ketamine, as novel and more efficacious antidepressant medications (Zarate and Machado-Vieira 2017; Abdallah et al. 2016). In this review, we discussed the pivotal role that ketamine played in the advancement of antidepressants, and its profound impact on enhancing this domain.

Search strategy or methodology

We used a search strategy approach to ensure a comprehensive assessment of current developments in the synthesis of antidepressant derivatives. We conducted a search using a mix of keywords, including “antidepressant derivatives,” “synthesis,” “mood disorders,” and “pharmacologic insights.” We searched PubMed, Scopus, and Google Scholar databases. The review considered studies that provided insights into the molecular elements of antidepressant activity, emphasized pharmacologic assessments, and outlined innovative synthetic approaches.

Epidemiology of depression

Based on the most recent data from the WHO in 2024, the prevalence of depression remains a significant global health concern, affecting approximately 4.2% of the global population. Among adults, the prevalence is 5.4%, and it increases to 6.1% among individuals aged 60 and above. This condition now affects an estimated 300 million people worldwide, highlighting its significant contribution to the global burden of disease and its role as a leading cause of disability (Kaggwa et al. 2022).

Depression continues to disproportionately affect women (8.1%) compared to men (5.1%). This gender disparity persists across almost all countries, with few exceptions. Recent data show that in Croatia and Finland, this gender gap is less pronounced, though still present. The incidence of depression varies significantly across Europe, with Iceland reporting the highest rate at 11.2% and the Czech Republic the lowest at 2.9% (Arias-de la Torre et al. 2021). In Poland, approximately 1.7 million people are currently living with depression. Among the working-age population, around 3.5% (equivalent to roughly 810,000 adult Poles) have experienced at least one depressive episode in their lifetime (Zalewska et al. 2022).

The incidence of 1-month major depression in the Asia–Pacific area varied between 1.3% and 5.5%, whereas prevalence of MDD ranged from 1.7 to 6.7% (Chiu 2004). Ogbo et al. determined that the prevalence of MDD in South Asia was 3.9%. Specifically, the prevalence rates are 3.9% in India, 4.4% in Bangladesh, 4.0% in Nepal, 3.0% in Pakistan, and 3.7% in Bhutan (Ogbo et al. 2018). Depression impacts 5% of the adult population in the Caribbean and Latin America. Furthermore, a majority of 60% of individuals do not undergo any form of medical intervention. Approximately 9.8% of the adult population in South Africa suffer from significant (clinical) depression at some stage in their lifetime (Dobrek and Glowacka 2023; Cuadros et al 2019).

Mechanism of action of antidepressants

The primary mechanism of action of antidepressants is the modulation of neurotransmitter systems in the brain, especially those involving monoamines like dopamine (DA), norepinephrine (NE), and serotonin (5-HT) as shown in Fig. 3 (Hillhouse et al. 2015). The most commonly prescribed antidepressants include serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), MAOIs, and selective serotonin reuptake inhibitors (SSRIs). SSRIs like sertraline and fluoxetine block serotonin reuptake in the synaptic cleft (Cui et al. 2024).

Fig. 3.

General mechanism of action of antidepressants

More serotonin is therefore accessible at postsynaptic receptors, which is believed to elevate mood and lessen symptoms of depression (Fig. 4). Similar to venlafaxine and duloxetine, SNRIs also block the reuptake of norepinephrine and serotonin, offering a more comprehensive range of effects that may be advantageous for certain individuals (Cui et al. 2024). Despite their adverse effect profile, TCAs continue to block norepinephrine and serotonin reuptake, but they also interact with other receptors, potentially leading to additional side effects (Sheffler et al 2023). On the other hand, MAOIs increase the amount of these neurotransmitters in the brain by blocking the monoamine oxidase enzyme, which breaks them down. Recent studies have shown that inflammation, the gut microbiome, and neurotrophic factors, including BDNF, are all involved in the pathophysiology of depression (Sansone et al. 2014). This implies that maintaining neuronal health and neuroplasticity may be crucial for the effective use of antidepressants. All things considered, the fundamental objective of anti-depressants is to restore the balance of neurotransmitters and encourage neuroplasticity, which will eventually enhance mood and cognitive performance in those who are depressed, even if the exact processes are still unclear and complicated (Behl et al. 2021).

Fig. 4.

Major warning signs and symptoms of depression

Current treatments of MDD

Recent progress in the field of antidepressant therapies involves the use of TCAs, like Elavil and MAOIs, like Nardil®. They enhance the synaptic levels of either two (NE and 5-HT) or all three (NE, 5-HT, and dopamine (DA) neurotransmitters (Gillman et al. 2007). The concurrent use of a SSRI such as Prozac^® and a serotonin reuptake transporter (SERT) inhibitor leads to an elevation in the synaptic concentration of 5-HT and prolongs its effects (Arias et al. 2021). Recent research indicates that the use of both bupropion, a substance that inhibits the Dopamine transporter (DAT), and either an SNRI or SSRI, which are substances that inhibit the absorption of serotonin and norepinephrine, respectively, is more effective in treating depression compared to using only one of these substances (Stahl et al. 2004). Three examples of drugs currently in Phase II clinical trials are SEP-225289 by Sepracor, DOV-21947 by DOV pharmaceutical, and NS-2359 by NeuroSearch. Cymbalta^®, a new class of antidepressants known as SNRIs, has been approved for the treatment of anxiety and depression in about 60% of patients (Wenga and Li 2010; Lucas et al. 2010).

The primary issues associated with current antidepressant medications encompass a delayed onset of therapeutic effects, significant adverse reactions, and a suboptimal response rate of less than 50% among patients (McIntyre et al. 2023). The etiology of depression and the mechanism of action of many antidepressant medications are not completely understood. Therefore, there remains a significant demand for expedited, secure, and more efficient remedies for depression (Blackburn et al. 2019). Recent efforts in pharmaceutical development have aimed to go beyond traditional monoamine-based approaches. These efforts have concentrated on exploring glutamatergic systems, neurotrophic factors, and the hypothalamic-pituitary axis (HPA), along with several other less well-understood targets (Fishback et al. 2010; Aboukhatwa and Undieh 2010).

Non-pharmacologictherapies are equally crucial in complementing the comprehensive treatment of depression. The procedures largely consist of psychotherapy methods such as naturopathic therapy, cognitive behavioral therapy, acupuncture, or physical activity interventions. Several studies have shown the positive effects of several dietary supplements in alleviating feelings of depression (Gautam et al. 2020; Farah et al. 2016). These products are formulated with polyunsaturated fatty acids (PUFAs), specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), as well as probiotics. This is based on the belief that inflammation and disruption of the gut-brain axis have a role in causing depression (Thurfah et al. 2022). Several dietary interventions have been studied for their potential use in treating depression. These interventions include specific nutrients like polyphenols, vitamins, and caffeine, as well as certain foods like nuts, fish, vegetables, fruit seeds, fermented products, and coffee/tea. In addition, dietary supplements like acetylcarnitine, S-adenosylmethionine (SAMe), amino acids, and creatine have also been investigated (Ortega et al. 2022).

In cases of severe depression that do not respond to traditional medication, advanced non-pharmacologicmethods like electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS) are employed (Leblhuber et al. 2021). Various literatures have shown that both treatments are effective in treating depression, with ECT being superior to rTMS. While ECT was shown to be the most effective treatment for MDD, it was also the treatment that was least well tolerated. On the other hand, rTMS was found to be the treatment that was most tolerated for MDD (Rizvi and Khan 2019; Chen et al 2019a, b).

Newer antidepressants for the treatment of MDD

Lanicemine

Lanicemine (AR-R 15896AR or AZD6765), developed by AstraZeneca, exhibits a pharmacologicprofile that closely resembles ketamine (Downey et al. 2016). However, it does not cause the same level of perceptual or cognitive side effects as ketamine when administered at dosages that generate equivalent effects on prefrontal cortex (PFC) activity (Guo et al. 2015; Bui et al. 2015). Preliminary phase Ib and 2a trials demonstrated indications of prompt onset antidepressant effects. A randomized controlled trial (RCT) was conducted with around 150 patients who were divided into three groups (Santi et al. 2024). These groups received either 100 mg lanicemine, 150-mg lanicemine, or a placebo three times a week for duration of 3 weeks. The results of the study demonstrated that both doses of lanicemine were more effective than the placebo in achieving the primary outcome that was predetermined (Sanacora et al. 2017). Curiously, there were indications suggesting the 100-mg dosage outperformed the 150-mg dosage. The 100-mg dosage of lanicemine exhibited substantial differences compared to the placebo at all visits. These differences in scores became apparent starting from week 2 and remained consistent until week 5 (Sanacora et al. 2014). In addition, it improved anxiety symptoms and exhibited significant alterations in clinical global impression (CGI) scores.

In contrast to ketamine, that produced instantaneous effects, lanicemine shown notable distinctions starting from the second week. However, this may be partially attributed to the higher placebo response observed in the lanicemine study (Downey et al. 2016). In a subsequent phase 2b trial, 302 participants were randomly assigned to one of three groups: a group that received 50 mg of lanicemine, a group that received 100 mg of lanicemine, and a placebo group (Sanacora et al. 2017). The treatment was administered three times a week for 3 weeks, followed by once a week for 3 weeks and then once every other week for 6 weeks. The trial did not demonstrate a higher effectiveness for either dosage of the medication in comparison to the placebo at the primary endpoint that was predefined, nor at any of the secondary endpoints (Lee et al. 2017a, b). Nevertheless, the analysis of this study is intricate because to the remarkably high percentage of placebo response, which stands at 39%, among individuals who had been previously treated but did not show any improvement (Jairath et al. 2016). The case of lanicemine serves as a reminder that compounds with innovative mechanisms of action may not necessarily demonstrate its efficacy in clinical trials (Qu et al. 2017).

Desvenlafaxine

Desvenlafaxine is a SNRI that was licensed by the Food and Drug Administration (FDA) in 2009 for the treatment of MDD in adults. It is an active metabolite of venlafaxine. Desvenlafaxine succinate is the form in which it is administered (Liebowitz and Tourian 2010). Desvenlafaxine induces selective inhibition of reuptake at the NE and 5-HT transporters, leading to an elevated extracellular concentration of NE and 5-HT. There is a greater preference for 5-HT transporters compared to NE transporters, with a roughly 10 times stronger affinity (Bruno et al. 2016). However, the affinity for dopamine transporters (DATs) is substantially weaker. Nevertheless, the antidepressant effect does not have any practical consequences on dopamine levels at the amounts needed to block the transporters for 5-HT and NE (Deecher et al. 2006).

Desvenlafaxine has been proven to be effective for treating MDD in multiple Randomized Controlled Trials (RCTs) and open-label trials with adult participants (Boyer et al. 2008; Clayton et al. 2013; Findling et al. 2016). It enhances the overall well-being, as assessed by improvements in emotional state, interpersonal connections, everyday activities, recreational pursuits, financial situation, and physical movement. It relieved depression symptoms in people with liver disease (Feinberg et al. 2010; Fabregas et al. 2014). A case report documented the remission of symptoms in a patient with social phobia who was administered a daily dose of 100 mg. A study without blinding was performed to evaluate the effectiveness of desvenlafaxine in children and teenagers. A dosage range of 50–200 mg was administered to children and adolescents with a positive outcome. Higher doses were linked to a greater occurrence of treatment-emergent adverse events (Findling et al. 2014).

Traxoprodil/ifenprodil

Traxoprodil (CP-101,606) is a compound that functions as an NMDA antagonist that specifically targets the NR2B subunit. An experiment conducted on rats shown that a solitary administration of CP-101606 improved the ability of the hippocampus to change and adapt in response to high-frequency stimulation 24 h after the administration of the drug 9 Yurkewicz et al. 2005). Preskorn et al. presented compelling clinical evidence about the antidepressant properties of traxoprodil in patients with treatment-resistant depression (TRD). The study included 30 patients, with 15 individuals in each treatment group. The results of this trial, which used a placebo control and a double-blind design, clearly demonstrated that patients who were administered CP-101606 experienced a more significant reduction in both MADRS and Hamilton depression rating scale (HDRS) ratings compared to the participants who received the placebo. Moreover, 78% and 32% of patients who received CP-101606 treatment maintained their responder status for 1 week and 30 days following the infusion, respectively (Poleszak et al. 2016).

Traxoprodil is a derivative of ifenprodil, which is classified as a phenylethanolamine chemical. Ifenprodil functions as an allosteric modulator of NMDA receptors, effectively inhibiting glutamate excitotoxicity in cell cultures (Ritter et al. 2023). It blocks NR2B NMDA receptors by enhancing the receptor’s responsiveness to negative regulation by protons. Traxoprodil does not have the psychotomimetic adverse effects that Ifenprodil has, despite both drugs having serotonergic and alpha-adrenergic activities (Hashimoto 2009; Mott et al. 1998). Preskorn et al. (2008) performed a study in which 6 patients in the treatment group experienced dissociative reactions. However, it is worth noting that two patients from the placebo group also had dissociative symptoms.

Levomilnacipran ER

Levomilnacipran ER, also known as 1S, 2R-milnacipran, is a SNRI that has been licensed by the FDA for treating MDD in adults. SNRIs, or SNRIs, all work by blocking the reabsorption of both 5-HT and NE, but they differ in how strongly they affect each transporter (Chen et al. 2015a, b). This has important consequences for their therapeutic use. Levomilnacipran ER is a more potent enantiomer of racemic milnacipran. It exhibits a potency that is twice as strong for inhibiting the reuptake of norepinephrine compared to serotonin. In addition, it selectively inhibits the reuptake of norepinephrine more than venlafaxine, duloxetine, and desvenlafaxine (Bakish et al. 2014).

The effectiveness of levomilnacipran for MDD and overall functioning has been demonstrated in five RCTs including adults, using dosages ranging from 40 to 120 mg per day. In a RCT conducted by Gommoll et al., (2014) there was a noticeable reduction in depression symptoms, although it did not achieve statistical significance. According to Asnis et al. (2013) there was a better response observed for doses of 80 mg and 120 mg compared to a dose of 40 mg.

D-cycloserine (DCS)

The study demonstrated that augmentation with a daily dose of 1 g of DCS (5) for TRD revealed that DCS acts as a partial agonist at the glycine modulatory site associated with the N-methyl-D-aspartate receptor (NMDAR) (Chen et al. 2019a, b). At elevated concentrations, it functions as an NMDAR antagonist. A total of twenty-six patients with treatment-resistant MDD took part in a 6-week parallel group experiment. The trial was double-blind and placebo-controlled, and involved the addition of a high dose (1000 mg/day) of DCS to the patients’ existing antidepressant prescription (Heresco-Levy et al. 2013). The amount of DCS was steadily increased over time. The DCS treatment was well-tolerated and did not cause any psychotomimetic effects. It effectively alleviated depressive symptoms, as indicated by the HDRS and Beck Depression Inventory (Frank et al. 2022). Out of the 13 individuals who had DCS treatment, 54% experienced a 50% drop in their HAMD score, compared to only 15% of the 13 patients who were randomly assigned to receive a placebo (p = 0.039). An important (p = 0.043) relationship was observed between the response to treatment and the levels of glycine in the serum before treatment (Heresco-Levy et al. 2013). In a previous trial conducted by the same group, the use of a lower dosage of DCS (250 mg/day) as an additional treatment to the existing antidepressant therapy did not result in any significant differences in outcome measures (Heresco-Levy et al. 2006).

Coumarin derivatives

Coumarins are a class of non-flavonoid polyphenols, namely o-hydroxycinnamic acid lactones, often referred to as “2H-chromen-2-one1,2-benzopyrone”. They belong to a category of aromatic phytochemicals that have a pleasant odor (El-Sawy et al. 2021). Coumarins and their derivatives have unique structures and are being employed for treating mental health conditions like anxiety, schizophrenia, and depression (Sashishara et al. 2015; Sahni et al. 2021; Rehuman et al. 2020; Delogu et al. 2014). The diverse pharmacologiceffects of coumarins and their derivatives are associated with their capacity to impede the formation of the mitotic spindle leading to cell death, inhibit myosin light chain kinase, and decrease tyrosine phosphorylation (Flores-Morales et al. 2023). In addition, their antidepressant properties may be attributed to their anti-inflammatory and antioxidant characteristics (Nabeel et al. 2021; Kilic 2022; Sinha 2022). Table 1 summarizes various coumarins derivatives and their inhibitory effects against monoamine oxidases.

Table 1.

The IC₅₀/PIC₅₀ values of various coumarins and their derivatives against monoamine oxidases and their inhibitory effects

Compound	Class/type	Mechanism of action	IC50/pIC50	Model (Human/animal)	Refs.
Auraptene	Natural coumarin	Inhibits monoamine oxidase, anti-inflammatory	34.60 μM	Animal (Rodent)	Jeong et al. (2006); Chang et al. (2021)
Umbelliferone	Natural coumarin	Antioxidant, neuroprotective	87.50 μM	Animal (rodent)
Isopsoralen	Furanocoumarin	Modulates neurotransmitters, neuroprotective	12.80 μM	Animal (rodent)	Kong et al. (2001)
Psoralen	Furanocoumarin	Inhibits monoamine oxidase	15.20 μM	Animal (rodent)	Kong et al. (2021)
Xanthotoxin	Furanocoumarin	Anti-inflammatory, modulates neurotransmitters	64.60 μM	Animal (rodent)	Carotti et al. (2002)
3,4-dihydro-2(1H)-quinolinone derivatives	Synthetic compound	Inhibits serotonin reuptake, antidepressant-like	6.89%	Animal (rodent)	Oshiro et al. (2000)
Lacinartin	Natural flavonoid	Modulates serotonin and dopamine receptors	9.20 μM	Animal (rodent)	Jo et al. (2002)
Scopoletin	Natural coumarin	Antioxidant, anti-inflammatory, neuroprotective	19.40 μg/mL	Animal (rodent)	Yung et al. (2001)
Decursin	Natural coumarin	Inhibits monoamine oxidase, neuroprotective	1.89 μM	Animal (rodent)	Lee et al. (2017a, b)

Arketamine

The NMDAR antagonist (R,S)-ketamine, a dissociative anesthetic, has garnered significant interest in the realm of psychiatric illnesses. Conclusive data has shown that (R,S)-ketamine has both long-lasting and fast-acting antidepressant effects in depressed individuals, post-traumatic stress disorder (PTSD), and bipolar disorder (BD) who do not respond to conventional treatments (Hashimoto 2022; Feder et al. 2021; Fava et al. 2020). (R,S)-ketamine is a racemic combination comprising of (S)-ketamine (also known as esketamine) and (R)-ketamine (also known as arketamine (6)). Despite its lesser affinity for the NMDAR, arketamine exhibits stronger and more enduring antidepressant-like effects compared to esketamine in mouse models of depression (Ebert et al. 1997; Yang et al. 2015).

In addition, it should be observed that the adverse reactions associated with arketamine are fewer in comparison to esketamine and (R,S)-ketamine (Chang et al. 2019). Collectively, arketamine would serve as an innovative, fast-acting antidepressant devoid of the adverse effects associated with esketamine and (R,S)-ketamine (Wei et al. 2022). Arketamine is a novel antidepressant that lacks the adverse effects associated with esketamine and (R,S)-ketamine. Arketamine not only exhibits antidepressant-like effects but it also has positive benefits on many animal models of neurologic illnesses, including Parkinson’s disease and multiple sclerosis (Wang et al. 2022).

Given that depression frequently manifests as a psychiatric symptom in individuals with neurologic illnesses, the administration of arketamine may potentially ameliorate depressed symptoms in these patients (Wei et al. 2022). The exact chemical and cellular mechanisms responsible for the antidepressant effects of (R,S)-ketamine and its enantiomers are still not fully understood. The communication between the brain and the body, specifically through the gut–microbiota–brain axis and the brain-spleen axis, may contribute to the positive effects of arketamine (Jelen et al. 2021; Zhang et al. 2021a, b; Scotton et al. 2022; Yang et al. 2017). However, additional research is required to fully understand this relationship (see Table 2).

Table 2.

List of antidepressant drugs under different phases of clinical trials, along with their mechanism of action, therapeutic indication, and their current trial number

Drug name	Mechanism of action	Therapeutic indication	Current status	Clinical trial number	Refs.
Psilocybin	Serotonin (5-HT2A) receptor agonist	Major depressive disorder	Phase II/III	NCT04670081	Husain et al. (2023)
Esketamine	NMDA receptor antagonist	Treatment-resistant depression	Approved/phase IV	NCT03434041	Zaki et al. (2023)
Zuranolone (SAGE-217)	GABA-A receptor positive allosteric modulator	Major depressive disorder	Phase III	NCT04442503	Hoffmann et al. (2020)
Rapastinel	NMDA receptor partial agonist	Major depressive disorder	Phase III (discontinued)	NCT03668600	Donello et al. (2019)
Amitifadine	Triple reuptake inhibitor (SERT, NET, DAT)	Major depressive disorder	Phase II	NCT02781315	Sharma et al. (2015)
BHV-5000	NMDA receptor modulator	Treatment-resistant depression	Phase II	NCT03080740	Moore et al. (2022)
Agomelatine	Melatonergic agonist and 5-HT2C antagonist	Major depressive disorder	Phase IV (Post-marketing)	NCT04355650	Olié et al. (2007)
JZP-386	GABA-A receptor modulator	Major depressive disorder	Phase I	NCT04691675	Luscher et al. (2011)
BTRX-246040	κ-opioid receptor antagonist	Major depressive disorder	Phase I/II	NCT04225155	Witkin et al. (2019)
MIN-117	Serotonin (5-HT1A) and dopamine (D2) receptor modulator	Major depressive disorder	Phase II	NCT02417188	Kaufman et al. (2016)
AXS-05	NMDA receptor antagonist and serotonin-norepinephrine reuptake inhibitor	Treatment-resistant depression	Phase III	NCT04408705	Iosifescu et al. (2022)
Seltorexant (JNJ-42847922)	Orexin-2 receptor antagonist	Major depressive disorder	Phase III	NCT04513922	Recourt et al. (2019)
Relamorelin	Ghrelin receptor agonist	Depression with gastroparesis	Phase II	NCT03751620	Patel et al. (2023)
Vilazodone	Serotonin reuptake inhibitor and 5-HT1A partial agonist	Major depressive disorder	Phase IV (approved)	NCT03030180	Sinha et al. (2021)
Vortioxetine	Serotonin modulator and stimulator	Major depressive disorder	Phase IV (approved)	NCT03829100	Connolly et al. (2016)

Newer heterocyclic derivatives

Piperazine derivatives

Piperazine is a hexagonal heterocyclic compound containing two nitrogen atoms positioned diagonally from each other. The Piperazine core is recognized for its significant significance in maintaining the pharmacokinetic (PK) profile of designer drugs in balance (Zhang et al. 2021a, b). Currently, there are multiple compounds containing piperazine that have been approved for the treatment of clinical depression. From a mechanistic standpoint, nearly all of them function as either partial or complete agonists of the 5-HT1A (Huang et al. 2017). Upon careful examination of their structural framework, it is noteworthy that the majority of FDA-approved antidepressants containing piperazine exhibit the existence of piperazine as a connecting element between the two aromatic/heteroaromatic sections (Patel and Won 2013; Lacivita et al. 2012).

Zareba et al. synthesized a collection of novels, large-sized Fananserin compounds and assessed their efficacy as antidepressants. The literature and virtual screening both indicate that the intended hits were obtained via SAR experiments for LCAP (longchain arylpiperazine derivatives). A total of eighteen new compounds were created and tested for their antidepressant effectiveness against the 5-HT7, 5-HT1A, and D2 isoforms of dopamine and serotonin receptors. The SAR (Structure–Activity Relationship) investigations demonstrated that as the alkyl chain length is increased up to six carbons and a fluorine substituent is introduced at the 2nd or 3rd position in the arylpiperazine, there is an enhanced affinity for the D2 and 5-HT1A receptors. The docking research revealed that these compounds can establish a hydrogen bond between the nitrogen atom in the carboxylic group of Asp106 and arylpiperazine ring (Zareba et al. 2019).

Gu et al. (2017) developed and created a range of aralkyl and arylalkanol piperazine derivatives with the intention of exploring their potential as antidepressant drugs. A total of 16 compounds were synthesized and assessed for their inhibitory effects on serotonin reuptake, as well as their affinities for the 5-HT7 and 5-HT1A receptors. Among all the compounds, compound 7 exhibited the greatest affinity for 5-HT7 and 5-HT1A receptors.

Ostrowska et al. (2020) created new compounds including piperazine and 6-acetyl-5-hydroxy-4,7-dimethylcoumarin. These compounds have a strong attraction to 5-HT1A, 5-HT2A, and D2 receptors. Compound 8 and compound 9 were found to have a strong attraction to 5-HT1A receptors in in vitro tests, having a Ki value of 1 nM. Both the synthesised compounds exhibited a strong binding ability to 5-HT2A receptors, with respective Ki values of 17.5 and 8 nM. Compounds 8 and 9 were observed to exhibit lower affinity towards D2 receptors, indicating their preference for serotonin receptors. In addition, both of the powerful substances underwent in vivo TST and FST experiments and were determined to be unsuccessful in mice, indicating that these substances lack any antidepressant potential. These adverse outcomes hindered their progress as a potential treatment for depression (Kumar et al. 2021a, b).

Indole derivatives

Indole derivatives are known to be serotoninergic modulators due to their structural similarity. The indole moiety is referred to as bioisosteres due to its resemblance in physical and chemical properties to other biological compounds (Munir et al. 2020). Similarity has been utilized in prototype drug development to enhance both the pharmacologicefficacy and the PK profile. The indole nucleus exhibits strong antidepressant effect. Different derivatives of indole and 5-HT are used as a framework for creating new chemical compounds that target the 5-HT1A receptor and the SERT (Ben-Daniel et al. 2008).

In their study, Cerda-Cavieres et al. (2020a, b) created and tested a collection of 27 compounds with indole structure. These compounds were designed to act as multitarget ligands, targeting the SERT, dopamine D2 receptor, and MAO-A. The goal of this research was to create new treatments for the treatment of MDD. All of the tested drugs exhibited a strong attraction to SERT in the nanomolar range, with five of them demonstrating Ki values ranging from 5 to 10 nM. Compound 10 exhibited similar affinities for both the D2 and SERT receptor, with a D2/SERT ratio of 3.6. This compound has the potential to be a multitarget lead for further improvement (Cerda-Cavieres et al. 2020a, b).

Kumar et al., (2021a, b) developed and created a range of piperazinyl derivatives that were modified with indole functional groups. The majority of the compounds exhibited strong inhibitory activity against MAO-A and demonstrated significant selectivity over MAO-B. The compounds showed high potential as reversible inhibitors of MAO-A, with IC50 values ranging from 0.11 ± 0.03 μM to 0.14 ± 0.02 μM.

Kaczor et al., (2023) conducted a study where they synthesized and extensively examined the structure and function of three indole derivatives (11–13) as ligands for serotonin 5-HT1A and 5-HT2A receptors. The protonatable nitrogen atom of the synthesised compounds and the conserved Asp (3.32) of the receptors created a salt bridge, which mediates the majority of the interaction between the ligands and the receptors. Molecular dynamics (MD) simulations showed that the ligands examined exhibit a high degree of stability in their respective binding sites, except for compound 12 when interacting with the serotonin 5-HT1A receptor (Kaczor et al. 2020).

The 5-HT system is a primary focus for antidepressant medications; the human serotonin transporter (hSERT) plays an important role in regulating the amounts of 5-HT in the synapses. Mattson et al., (2005) conducted the synthesis of a range of indole cyclopropylmethylamines. A subset of these produced compounds was then assessed for their antidepressant effects. Based on the structure–activity relationship, the presence of nitrile substituents at the 5th and 7th positions of the indole ring resulted in a strong affinity for hSERT. However, when the indole ring was substituted at the N-1 position with a methyl or ethyl group, the affinity for hSERT decreased by 10–30 times (Siddiqui et al. 2011).

Piperidine derivatives

The piperidine ring is a widely distributed molecular structure. Piperidine-containing chemicals play an important role in biology and medicine. The biological characteristics of piperidines are greatly influenced by the nature and position of substituents on the heterocyclic ring. Clinical and preclinical investigations have referenced several N-heterocyclic piperidine molecules (Takeuchi et al. 2003; Kallstrom and Leino 2008). Kaya et al., (2022) developed new compounds derived from piperidine and examined their effects on depression-like symptoms. The compounds were assessed for their antidepressant-like effects using TST and FST at a dosage of 50 mg/kg. Furthermore, potential changes in the locomotor behaviors of mice were assessed using activity cage measures. The results demonstrated that compounds 14a-14d effectively decreased the immobility time of mice in both antidepressant activity-screening tests, suggesting that these derivatives had antidepressant-like properties (Bogdanova et al. 2013).

In their study, Yuan et al. (2022) synthesized a range of innovative derivatives of 1-(1-benzoylpiperidin-4-yl) methanamine and assessed their ability to block serotonin reuptake and their affinities for binding to the 5-HT1A receptor. The findings demonstrated that the synthesized compounds displayed potent suppression of serotonin reuptake and significant binding affinity for 5-HT1A receptor. In vitro, the compounds demonstrated favorable metabolic stability and displayed possible antidepressant-like effects in mice when tested in the FST and TST (Marcinkowska et al. 2021).

Pyrimidine derivatives

Pyrimidine and its derivatives have garnered significant attention due to its diverse range of key pharmacologiceffects and favorable pharmacokinetic features (Arias-Gómez et al. 2021). Krol et al., (2021) synthesized two sets of new pyrido-pyrimidine (15a-i) and tetrahydropyrido-pyrimidine (16a-i) compounds. In vitro radioligand binding experiments were used to evaluate the affinities of synthesised compounds for the 5-HT1A receptor and SERT. All derivatives in the series exhibited exceptionally strong binding affinities for the 5-HT1A receptor, while generally displaying weak binding affinities for the SERT protein.

A study evaluated the anticonvulsant and antidepressant effects of a series of derivatives (17) of “5-alkoxytetrazolo [1, 5-c] thieno [2, 3-e] pyrimidine”. The compound 17 was the most effective at a dosage of 100 mg/kg. It shortened the immobility period by 51.62% (Wang et al. 2012). Kim et al., (2010) produced a collection of pyrimidine 4-carboxamide derivatives that include arylpiperazine. An assessment was conducted on several manufactured compounds to determine their level of affinity for serotonin receptors and transporters. The researchers conducted in vitro and structure–activity relationship (SAR) tests and concluded that compound (18) had the highest potency in this series, with an IC₅₀ value greater than 10 μM.

Thiadiazole derivatives

The thiadiazole system is a cyclic compound that is similar to thiosemicarbazide and has the N=C=S linkage, which is responsible for its toxic properties (Serban, et al. 2018). Thiadiazole is a compound that is formed from thiophene by substituting two –CH= groups with pyridine-type nitrogen (–N=). It exists in four different isomeric forms, which are determined by the locations of the nitrogen atoms (Sah et al. 2014). Several synthetic products have been developed using the thiadiazole nucleus, which exhibit a wide range of pharmacologicactivities. For instance, KC12291 has demonstrated cardioprotective effects, while small heterocyclic thiadiazolidinones (TDZD) are the first inhibitors of glycogen synthase kinase 3b that do not compete with ATP. The thiadiazole derivative compounds exhibited strong antidepressant and anxiolytic effects (Castro et al. 2006; Lotfi et al. 2020).

In their study, Saglik et al. (2020) developed a range of 1,3,4-thiadiazole derivatives that contain different alkyl/arylamine groups. These compounds were specifically designed and produced as inhibitors of MAO. The compounds exhibited greater selectivity against hMAO-A compared to hMAO-B. The majority of the compounds had half maximum inhibitory concentration (IC50) values that were lower than the IC50 value of the commonly used medicine moclobemide (IC50 = 4.664 μM). Compound 19 had the highest level of activity, with an IC50 value of 0.060 μM and it also exhibited a comparable inhibitory profile to clorgyline. Compound 19 exhibited a reversible and competitive inhibitory profile, showing selectivity towards MAO-A (Osmaniye et al. 2021).

Sharma et al., (2011) synthesised a novel series of derivatives of “2-amino-5-sulfanyl-1,3,4-thiadiazole”. The recently produced chemicals were identified using analytical and spectroscopic techniques. The compounds underwent screening to assess their activity on the central nervous system. Each of the synthesized compounds demonstrated substantial antidepressant, anxiolytic, and anticonvulsant effects when compared to the reference medications. Jatav et al., (2008) produced a range of “3-[5-substituted phenyl-1, 3, 4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones”. Among the 18 synthesised compounds, compound 20 had significant antidepressant efficacy when tested using the forced swim test method.

Pyrazoline derivatives

Pyrazoline exhibits a distinctive structure consisting of a ring of five atoms, including at least one heteroatom. Pyrazolines are a significant group of heterocycles known for their strong biological and pharmacologiceffects (Barsoum and Girgis 2009). Aggarwal et al. (2021) conducted a synthesis of novel pyrazoline derivatives and assessed their effectiveness as anti-depressants through In-silico and In-vivo experiments. The cyclization of chalcones with phenylhydrazine in glacial acetic acid resulted in the production of pyrazoline derivatives.

A study on the effectiveness of antidepressants was conducted using the TST and FST in live subjects. The confirmation of the likely method by which the chemicals demonstrate neuropharmacological interactions arose from their contact with the residues of the binding sites, specifically ASP 46. This demonstrates that the chemicals possess a strong attraction to the MAO-A target protein (Finberg et al. 2016). Siddiqui et al. (2009) developed and created a series of “N,3-(substituted diphenyl)-5-phenyl-1H-pyrazoline2-carbothioamide derivatives”. Compound (21a) and compound (21b) both shown a substantial reduction in the immobility time at a dose of 25 mg/kg, when compared to the control group. All the chemical derivatives are shown in Figs. 5 and 6.

Fig. 5.

Chemical structures of designed derivatives. (1) Lanicemine (2) Desvenlafaxine (3) Traxoprodil (4) Levomilnacipran ER (5) D-cycloserine (DCS) (6) Arketamine (7–9) Piperazine derivatives (10–13) Indole derivatives (14) Piperidine Derivatives

Fig. 6.

Chemical structures of designed derivatives. (15–18) Pyrimidine derivatives (19–20) Thiadiazole derivatives (21) Pyrazoline derivatives

Miscellaneous agents

Over the past 2 decades, several new drugs with different ways of working have been studied for treating MDD. MK0869, a substance P antagonist, was first welcomed with high anticipation as a ground breaking approach in the management of depression (Humes et al. 2024). Proof-of-concept research provided evidence of its effectiveness and favourable tolerability in treating MDD. However, in later trials, the medicine did not demonstrate substantial effects when compared to a placebo, leading to the discontinuation of its development as a therapy for MDD (Al-Harbi et al. 2012). In addition, the effectiveness of SSR149415, a medication that blocks the vasopressin 1b receptor, in treating depression has been assessed in three clinical trials, yielding varied outcomes (Argyropoulos and Nutt 2000; Griebel et al. 2012).

Moreover, some nutraceuticals have been examined for their potential involvement in the management of depression. Many research and systematic reviews have examined the effectiveness of omega-3 PUFAs in treating and preventing depressive illnesses (Wani et al. 2015). The results of a recent meta-analysis provide evidence for the beneficial effects of omega-3 polyunsaturated fatty acid supplementation in treating MDD. However, the benefits appear to be limited to formulations that contain more than 60% EPA, as opposed to formulations that only contain DHA or a higher proportion of DHA (Liao et al. 2019).

SAMe is an amino acid metabolite found inside cells. It acts as a co-substrate for enzymes involved in the production of hormones and neurotransmitters. SAMe has been investigated as a potential treatment for individuals with depression (Mato et al. 2013). In addition, the use of methylfolate as a supplement to antidepressants has shown possible benefits in treating MDD according to various meta-analyses (Sarris et al. 2020; Firth et al. 2019). However, other writers, like Roberts et al (2018), have highlighted the limited methodological quality of the studies available.

Future perspective

Research is continuously revealing new therapeutic agents and innovative methodologies, indicating promising prospects for the treatment of major depressive disorder (MDD). Future therapies may increasingly concentrate on personalized medicine, which involves customizing therapy to specific patient profiles based on genetic, biochemical, and psychologic characteristics. Once we achieve a fuller understanding of the neurobiological pathways underlying depression, this will become possible. In addition, the use of cutting-edge technology, such as artificial intelligence and machine learning, has the potential to improve drug development procedures, which would ultimately result in the discovery of compounds that are more effective and have fewer adverse effects. As the discipline develops, there is also the possibility of combining pharmaceutical therapies with psychotherapy tactics and lifestyle adjustments, which would result in a more comprehensive approach to the management of depression. The end objective is to enhance patient outcomes and quality of life by creating treatments that not only ease symptoms but also address the fundamental causes of MDD. All those suffering from this terrible ailment will have access to effective therapy in future.

Conclusion

The development of depression is influenced not just by serotonin, but also by glutamate, histamine, noradrenaline, and other receptors, including their subtypes. Monotherapeutic medicines are insufficient for the treatment and management of this intricate disease. In addition, these drugs that target a particular specific area are also associated with diverse adverse effects and toxicities. The significant progress in the healthcare industry has resulted in the creation of multiple therapeutic medicines that operate through various mechanisms and mitigate depression to varying degrees. An extensive examination of referenced literature has uncovered that compounds containing two or more active pharmacophores linked by an optimal spacer are likely to have an effect on many biological targets. Specifically, combinations of substituted piperazine with indole or purine, connected by an ideal spacer, provide powerful compounds with a diverse range of target-binding abilities. These molecules show potential for significant biological effects, improved effectiveness, and little toxicity. These compounds have exhibited exceptional binding affinities to various receptors implicated in the disease’s etiology. In vivo and in silico investigations have further corroborated these findings. This compilation may be useful for medicinal chemists and drug developers seeking insights into the key structural characteristics that contribute to the biological activity associated with depression. These insights can be applied to the rational design of drugs targeting depression. These discoveries can be used by researchers as supporting evidence for the development of more effective, powerful, and safe chemicals to address complex illnesses similar to depression.

Abbreviations

MDD

Major depressive disorder

IC50

Half maximal inhibitory concentration

NMDA

N-methyl-D-aspartate

5-HT

5-Hydroxytryptamine (serotonin)

Funding

No funding applicable.

Declarations

Conflict of interest

Authors are required to disclose financial or non-financial interests that are directly or indirectly related to the work submitted for publication. The authors declare no conflicts of interest.