Progress on the neurotrophic effects of antidepressant drugs

Abstract

Major depressive disorder (MDD) is among the most common mental disorders, with clinical symptoms involving multiple aspects such as mood, cognition, physiology, and behavior. Based on the data from the World Health Organization, approximately one-fifth of individuals worldwide suffer from depression, making it the fourth leading cause of disability globally. MDD pathogenesis is overly complex. The traditional “monoamine hypothesis” suggests that depression is primarily associated with low levels of monoamine neurotransmitters. Recent research breakthroughs in the study of MDD’s etiology have resulted in the proposal of the “neurotrophic hypothesis” as an explanation for this disorder. This hypothesis suggests that, beyond alterations in neurotransmitters, the onset of depression is primarily associated with a decline in the expression of neurotrophic factors and a decrease in adult hippocampal neurogenesis. This may eventually result in hippocampal atrophy in individuals with depression. Conversely, antidepressant treatment can elevate the expression of neurotrophic factors and enhance adult hippocampal neurogenesis, thereby reversing or blocking the effects of stress on hippocampal atrophy and improving depressive symptoms. Clinical studies have demonstrated that patients with MDD exhibit reduced hippocampal volume. The magnitude of reduction is positively correlated with depression duration, which may be linked to impaired hippocampal neurogenesis. This article reviews the research progress on the neurotrophic effects of antidepressant drugs.

Key Words: Major depressive disorder; Neurotrophic factors; Synaptic plasticity; Neurogenesis; Antidepressant drugs

Core Tip: Major depressive disorder (MDD) is a complex disorder involving multiple neurotransmitters and brain regions. In patients with MDD, alterations may occur in the stability and functionality of these neural networks, extending beyond mere chemical imbalances. Antidepressants have neurotrophic effects that can enhance synaptic connections and stimulate the growth of new neurons, thus helping restore the function of neural networks. Synaptic and neurogenic enhancements induced by antidepressants require time to manifest and develop. These advances may yield more effective and safer antidepressants and improve the use of existing medications for patients with MDD.

INTRODUCTION

Major depressive disorder (MDD) is a type of mood disorder characterized primarily by persistent and significant low mood, slowed thinking, reduced volitional activity, and physical discomfort[1]. The primary clinical symptoms of MDD include a depressed mood, a lack of interest, and anhedonia, which is the inability to feel pleasure. These are often accompanied by other symptoms, such as reduced appetite, waking up early in the morning, and unintentional weight loss. Furthermore, patients with MDD frequently experience cognitive dysfunction, along with somatic symptoms, suicidal ideation, and suicidal behaviors[2]. Studies indicate that more than 19 million adults in the United States experience depression, with the costs for both direct and indirect treatments surpassing 30 billion dollar[3]. In China, more than 26 million people are affected by depression, with an incidence rate of about 2%. It is concerning that 90% of individuals are unaware of their condition. Moreover, the annual number of suicide deaths attributed to depression is estimated to be 1 million[4]. MDD not only has a profound psychological impact but also heightens the risk of developing other health conditions, such as cardiovascular disorders, diabetes, obesity, Alzheimer’s disease, and cancer. Consequently, the overall burden of disease increases, compounding the challenges faced by individuals, families, and society at large[5].

The existing clinical treatment for MDD still primarily relies on pharmacological intervention. Commonly used antidepressants include the following: Tricyclic antidepressants, such as imipramine, amitriptyline, and doxepin; selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine, and sertraline; serotonin-norepinephrine reuptake inhibitors, such as venlafaxine and milnacipran; noradrenergic and specific serotonergic antidepressants, such as mirtazapine[6]. Although antidepressants can immediately increase neurotransmitter concentrations in the synaptic cleft, their therapeutic effects typically take 2-3 weeks to manifest. Moreover, treatment efficacy varies depending on factors such as gender, age, and the specific drug used, suggesting the limitations of the monoamine hypothesis. Furthermore, existing antidepressants may act on other molecular targets beyond monoamine modulation[7,8].

Recent advances in understanding MDD have led to the formulation of the neurotrophic hypothesis[9,10]. This hypothesis posits that, beyond changes in neurotransmitters, the onset of MDD is primarily associated with decreased expression of neurotrophic factors and reduced adult hippocampal neurogenesis. These changes may lead to hippocampal atrophy in patients experiencing depression. Conversely, antidepressant treatment can elevate the expression of neurotrophic factors and enhance adult hippocampal neurogenesis, thereby reversing or blocking the effects of stress on hippocampal atrophy and improving depressive symptoms. Clinical studies have demonstrated that patients with MDD exhibit reduced hippocampal volume. The extent of reduction is directly linked to MDD duration, which might be associated with disrupted hippocampal neurogenesis. Consequently, promoting hippocampal neurogenesis is essential for the behavioral improvement induced by antidepressant treatment[11,12]. This article reviews the research progress on the neurotrophic effects of antidepressant drugs.

Neurotrophic factors are a group of polypeptide molecules that exert specific trophic effects on neural cells. They include brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor, neurotrophin-3 (NT-3), neurotrophin-4, and more than 20 others. These factors are vital for preserving nervous system integrity, guiding neural differentiation, supporting neuronal survival, driving development and maturation, regulating synapse formation, and modulating synaptic plasticity[13].

In summary, current research mainly focuses on single pathways or lacks systematic integration between preclinical and clinical studies. Therefore, this article aims to address this research gap through synthesizing evidence on the neurotrophic effects of antidepressants, reviewing key signaling pathways such as BDNF/tropomyosin receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR)-BDNF, and exploring how these mechanisms contribute to the depressive symptom improvement. Ultimately, providing insights for developing future depression treatment strategies based on neurotrophic mechanisms.

ANTIDEPRESSANT DRUGS AND NEUROTROPHIC FACTORS

Animal and cellular studies

Among the neurotrophic factors studied in MDD, BDNF has received the most attention. BDNF, one of the most extensively distributed neurotrophic factors, is abundantly present in the mammalian brain, especially within the cerebral cortex and hippocampus. BDNF is vital for encouraging synaptic development, enhancing synaptic connections, adjusting neuronal plasticity, and providing neuroprotective benefits while aiding in neuronal recovery following injury[14,15]. BDNF and NT-3 improve the function and growth of serotonergic neurons in the adult brain. Chronic infusion of BDNF and NT-3 into the midbrain of rats increases serotonin turnover and norepinephrine levels in several forebrain regions, including the neocortex, basal ganglia, and hippocampus[16,17]. The significant effects of BDNF and NT-3 on the function, growth, and regeneration of serotonergic neurons suggest a potential link between neurotrophic factors and MDD[18]. In animal models subjected to stress, such as those used in learned helplessness and forced swim tests, the continuous infusion of BDNF into the dorsal raphe nucleus (a region where serotonin-producing neurons are concentrated) results in antidepressant-like effects akin to those observed with conventional antidepressants[19]. While exogenous BDNF administration mimics antidepressant effects, it remains unclear whether endogenous neurotrophic factors are involved in MDD treatment.

Escitalopram treatment significantly increased hippocampus neurotransmitter and neurotrophic factor levels, stimulated hippocampus neurogenesis, and relieved central nervous system (CNS) microglial overactivation in chronic mild stress mice[20]. Duman et al[21] demonstrated that several classes of antidepressants, including serotonin or norepinephrine reuptake inhibitors and monoamine oxidase inhibitors, increase BDNF mRNA expression in the rat hippocampus. Saliently, this upregulation occurs only after three weeks of treatment, consistent with the delayed therapeutic onset observed in clinical MDD treatment. These antidepressants also elevate mRNA expression of TrkB, the high-affinity tyrosine kinase receptor for BDNF[22]. Unlike antidepressants, the prolonged use of psychostimulants, such as cocaine or other psychoactive substances, does not lead to an increase in BDNF or TrkB levels[23]. In rats treated with a nanotransferosomal gel containing paroxetine, improved behavior was observed, characterized by a decrease in immobility time and the presence of clearly defined neuronal morphology in Nissl-stained brain tissues[24]. Fluoxetine acts on astrocytes and increases exocytosis of ATP. This has therapeutic effects via BDNF-dependent mechanisms[25].

Electroconvulsive therapy is clinically employed to treat severe depression. In animal studies simulating this therapy, seizures induced either chemically, such as with pilocarpine, or electrically, led to an increase in BDNF mRNA levels in the hippocampus, cortex, and various other brain regions[26,27]. Similar to antidepressants, electroconvulsive therapy prevents stress-induced decreases in hippocampal BDNF mRNA. Lithium and valproate are mood stabilizers commonly used to treat and prevent mood disorders. After chronic administration, they increase BDNF expression in the rat brain, especially in the hippocampus and prefrontal cortex. They also promote hippocampal neurogenesis and partial synaptic remodeling in rodents[28].

GDNF is a member of the transforming growth factor-β superfamily and is widely distributed in the mammalian brain. It promotes the survival of various CNS neurons, including midbrain dopaminergic neurons, motor neurons, and norepinephrine neurons in the locus coeruleus. GDNF also enhances the survival of peripheral neurons, including sympathetic, parasympathetic, sensory, and enteric neurons. GDNF exerts protective effects on cultured or developing cholinergic motor neurons, increases cholinesterase activity, and is recognized as the most potent neurotrophic factor for cholinergic motor neurons identified to date[29]. In animal studies, antidepressants have not been found to affect GDNF or its receptor mRNA expression[30]. However, lithium has been reported to increase GDNF protein levels in the brains of depressive rat models[31]. Research on animal models of electroconvulsive therapy has yielded mixed results. While some studies report that electroconvulsive stimulation decreased GDNF concentration in the rat hippocampus and striatum[32], others found no significant effect on hippocampal GDNF mRNA expression. However, they observed a marked increase in GDNF receptor mRNA expression[30]. In vitro studies using C6 glioma cell lines and cultured rat astrocytes have demonstrated that serotonin, antidepressants, and mood stabilizers (lithium and valproate) can significantly increase GDNF secretion in a dose- and time-dependent manner[33-36]. These inconsistent results likely reflect differences in patients populations, disease stages and drug exposure. For instance, peripheral GDNF levels may fluctuate dynamically with emotional states. Studies indicate that levels decrease during remission or chronic phases but increase during acute emotional episodes[37,38]. Meanwhile, variations in biological samples, such as serum and plasma, and detection methods further contribute to result heterogeneity[39]. Additionally, some studies suggest that blocking the extracellular signal-regulated kinase pathway partially attenuates fluoxetine-induced upregulation of GDNF mRNA expression in astrocytes, highlighting the important role of extracellular signal-regulated kinase in cell growth and survival[40]. Overall, changes in GDNF levels may reflect state or treatment dependent phenomena rather than stable trait markers.

Combining findings from animal and cellular studies, both BDNF and GDNF play crucial roles in maintaining neuronal survival, synaptic plasticity, and stress recovery. BDNF primarily promotes dendritic growth and synaptic remodeling through the TrkB-mTOR signaling pathway, while GDNF exerts antioxidant effects. These findings provide evidence for understanding the mechanistic basis of neurotrophic factors in antidepressant actions and establish a crucial bridge for subsequent clinical translation.

Clinical studies

Clinical studies have found that serum BDNF levels in patients with MDD are lower than in healthy controls[41,42]. BDNF is abundant in human plasma, with a significant portion localized within platelets. Studies indicate that a reduction in serum BDNF levels in individuals with MDD could be linked to a deficiency in BDNF release from platelets[43]. BDNF is linked to how individuals with mood disorders respond to antidepressant medications[44]. Aydemir et al[45] found that patients with untreated MDD exhibited lower serum BDNF than controls. Following 12 weeks of antidepressant treatment, BDNF returned to the normal range. Similarly, Gonul et al[46] reported that serum BDNF in patients with MDD returned to normal after eight weeks of antidepressant therapy. Factors such as recurrent depressive episodes, suicidal behavior, and psychotic symptoms may also influence plasma BDNF levels[47-50]. Plasma BDNF levels remained unchanged before and after infusion with non-antidepressants such as scopolamine[51]. BDNF lysis pathway could play a role in MDD pathogenesis and the processes involved in the therapeutic efficacy of antidepressant treatments. BDNF could serve as a diagnostic biomarker panel for MDD[52]. A notable finding was that serum BDNF levels increased in all patients treated with antidepressants, regardless of clinical improvement. Furthermore, the magnitude of increase in BDNF levels did not differ significantly between responders and non-responders[53]. Studies have demonstrated that the BDNF/TrkB signaling pathway plays a crucial role in the effectiveness of antidepressants and partly influences how sensitive individuals are to SSRIs and other commonly used antidepressant medications[54]. This suggests that enhancing BDNF/TrkB pathway signaling may represent the key mechanism underlying antidepressant efficacy.

Takebayashi et al[37] measured serum GDNF in patients with MDD in partial or full remission and in bipolar disorder, and found significantly lower levels than in healthy controls. Conversely, Rosa et al[38] reported increased serum GDNF protein concentrations during both manic and depressive episodes in bipolar disorder patients. Otsuki et al[55] reported reduced peripheral blood GDNF mRNA expression during depressive episodes in patients with MDD; in remission, expression did not differ from controls. Michel et al[56] observed that patients with MDD exhibited higher GDNF levels in the parietal cortex but lower levels in the hippocampus when compared with matched controls. A strong body of evidence indicates an association between GDNF and MDD. However, clinical studies have predominantly focused on serum assays. In contrast to BDNF, GDNF is a sizable protein that is unable to pass through the blood-brain barrier. Although serum GDNF does not directly mirror brain concentrations, animal studies indicate neuroprotective effects. In rats, the striatal injection of recombinant human GDNF increases the activity of superoxide dismutase, catalase, and glutathione peroxidase[57]. These findings imply that peripheral GDNF may confer protection against oxidative damage and influence depression pathogenesis through indirect antioxidant effects in the CNS.

Recent therapeutic advances have extended beyond traditional SSRIs/serotonin-norepinephrine reuptake inhibitors to include N-methyl-D-aspartate (NMDA) receptor antagonists such as esketamine. These agents demonstrate rapid clinical benefits in treatment-resistant depression (TRD) and play a role in neurotrophic mechanisms distinct from classical monoaminergic drugs. Esketamine transiently blocks NMDA receptors, causing a surge in cortical glutamate release. This promotes BDNF release and TrkB signaling cascades. These changes rapidly activate mTOR-dependent protein synthesis pathways, promote synaptic formation in prefrontal-hippocampal circuits, and correlate with behavioral improvements[58,59]. Additionally, TrkB agonists have demonstrated neurotrophic targeting potential in current research. Among these, 7,8-dihydroxyflavone has been identified as a selective TrkB agonist capable of directly activating the BDNF-TrkB signaling pathway, thereby enhancing synaptic plasticity and exhibiting antidepressant-like effects in preclinical models[60].

Similar to pharmacological interventions, an increasing number of studies are delving into non-pharmacological interventions, with multiple non-pharmacological approaches demonstrated to participate in neurotrophic and neuroplastic processes. For instance, electroconvulsive therapy enhances central and peripheral neurotrophic markers, such as BDNF and vascular endothelial growth factor[61], and promotes hippocampal neurogenesis[62]. These effects may underpin the mechanism by which this treatment exhibits higher efficacy in TRD. Additionally, more environment-based adjunct therapies, such as exercise intervention and music therapy, have also been shown to exert effects through neurotrophic mechanisms. For instance, exercise intervention can stably increase peripheral BDNF levels and is associated with improved hippocampal function and mood[63,64]. Notably, non-pharmacological and pharmacological interventions exhibit overlapping mechanisms across pathways such as BDNF-TrkB and mTOR. Therefore, combining both approaches may yield synergistic effects in ameliorating depressive symptoms. To integrate these convergence mechanisms, we have introduced a new mechanism integration diagram (Figure 1).

Figure 1 Schematic diagram of mechanistic integration of antidepressant therapy via the brain-derived neurotrophic factor-tropomyosin receptor kinase B and mammalian target of rapamycin pathways. SSRI: Selective serotonin reuptake inhibitor; NMDA: N-methyl-D-aspartate; ECT: Electroconvulsive therapy; BDNF: Brain-derived neurotrophic factor; mTOR: Mammalian target of rapamycin; TrkB: Tropomyosin receptor kinase B; GDNF: Glial cell line-derived neurotrophic factor; HNK: Hydroxynorketamine; AMPAR: Α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; VEGF: Vascular endothelial growth factor; DG: Dentate gyrus; MDD: Major depressive disorder.

It is particularly noteworthy that the neurotrophic mechanisms differ across clinical subtypes. For instance, patients with TRD often exhibit lower BDNF levels[65], and this population typically responds more strongly to interventions that potently induce synaptogenesis, such as electroconvulsive therapy or ketamine/dextroketamine[66,67]. In contrast, MDD with anxiety frequently presents with hyperreactivity in amygdala/striatal-limbic regions and abnormal hypothalamic-pituitary-adrenal axis dynamics. These alterations suppress BDNF expression and shift plasticity toward stress-related remodeling rather than reparative synaptogenesis[68,69]. These distinct mechanisms suggest that future trials should pre-specify subtype analyses and incorporate mechanistic biomarkers, such as BDNF/TrkB phosphorylation, mTOR activity.

ANTIDEPRESSANT DRUGS AND SYNAPTIC PLASTICITY

In the normal nervous system, synapses interconnect with each other, establishing connections between isolated neurons and forming intricate neural pathways. Excitatory and inhibitory synapses in the brain mutually regulate each other to maintain the homeostasis of signal transmission. When the body is subjected to intense or prolonged external stimuli, this homeostasis is disrupted, leading to the reformation of synapses with different properties. The resulting facilitation or inhibition of signal transmission is referred to as synaptic plasticity[70]. Synaptic plasticity manifests in two forms: Structural plasticity and functional plasticity. Structural plasticity refers to changes in the morphology, structure, and number of synapses that occur following neuronal stimulation, resulting in synaptic remodeling that influences brain function. Functional plasticity can be further divided into two categories: Long-term depression, a sustained decrease in synaptic transmission efficiency that occurs after repeated neuronal stimulation, and long-term potentiation (LTP), a sustained increase in synaptic transmission efficiency that occurs after repeated neuronal stimulation. LTP: A persistent enhancement of synaptic transmission efficiency due to increased postsynaptic potential after stimulating presynaptic neuron terminals. LTP is induced when presynaptic stimulation coincides with postsynaptic depolarization, and is generated and maintained through a combination of presynaptic and postsynaptic mechanisms[71]. LTP and long-term depression are critical manifestations of synaptic plasticity, serving as key physiological mechanisms underlying cognition and memory[72]. Antidepressant drugs promote neuronal plasticity, and activation of BDNF signaling through its receptor, neuronal receptor tyrosine kinase 2, is among the critical steps in this process[73].

Prolonged transmission of nociceptive signals induces structural and functional plasticity changes in higher brain regions, such as the prefrontal cortex[74], amygdala[75], dentate gyrus[76], and anterior cingulate cortex[77]. These changes include neuronal atrophy, reduced dendritic complexity, and decreased dendritic spine density, resulting in depression-like symptoms[78,79]. The size, number, and morphology of dendritic spines play a crucial role in synaptic plasticity, learning, and memory[80]. Depressive symptoms, such as anhedonia (loss of pleasure), and overall severity are closely linked to brain volume reductions and changes in synaptic plasticity in patients with MDD[81]. Stress-induced neuronal atrophy and dysfunction in glutamatergic synaptic transmission are key factors in depressive pathology[4,82]. Studies have found that when the gamma-aminobutyric acid B receptor agonist baclofen is applied to neurons treated with NMDA receptor antagonists, it enhances resting dendritic calcium signaling via gamma-aminobutyric acid B receptor activation, subsequently upregulating the mTOR activity[83]. The mTOR-BDNF signaling pathway, a critical regulator of synaptic plasticity, plays a pivotal role in ketamine’s antidepressant effects[84,85]. Ketamine activates mTOR, which in turn stimulates downstream ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein, promoting the synthesis of BDNF and synaptic proteins (glutamate receptor 1 and postsynaptic density protein 95). As a key regulator of synaptogenesis, BDNF binds to and activates TrkB, fostering dendritic spine growth and maintaining synaptic plasticity[86,87]. By blocking NMDA receptors, ketamine decreases the activity of GABAergic neurons, leading to an increase in glutamate release. This process boosts synaptic plasticity and promotes neuronal growth, thereby alleviating depressive symptoms[88,89].

Zanos et al[90] further discovered that (2R,6R)-hydroxynorketamine can induce a rapid enhancement of glutamatergic signaling. This involves increased presynaptic glutamate release and its binding to postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-gated channels, allowing sodium ions to enter the cell[91]. This process boosts the activity of hippocampal afferents, increases the levels of glutamate A1 and glutamate A2 in hippocampal synapses, and markedly alleviates depressive symptoms. Antidepressants, such as venlafaxine, mirtazapine, fluoxetine, and desipramine, are capable of reversing the reduction in BDNF protein levels, encouraging synaptic development, promoting neurogenesis, and leading to an enhancement of mood[20,92]. Specifically, fluoxetine acts on multiple aspects of neuroplasticity mechanisms by enhancing the secretion of various neurotrophic factors, facilitating the formation of new synapses, and promoting neuronal regeneration, all of which contribute to neural recovery[93-95]. Furthermore, after undergoing antidepressant therapy, notable alterations in the levels of proteins associated with synapses often occur, including synaptophysin-1, microtubule-associated protein-2, synaptotagmib-1, and postsynaptic density protein 95[96-100]. These proteins serve as biomarkers for neuronal synaptic plasticity alterations and are likely involved in both the pathogenesis and recovery of mood and cognitive-related psychiatric disorders, including depression. Emerging evidence suggests that depression arises from dysregulation not only in central neurotransmitter systems but also in postsynaptic signaling cascades and transcriptional regulation, resulting in region-specific neurotrophic deficits and compromised neural plasticity[101]. Importantly, BDNF appears to function as a molecular transducer that mechanistically links antidepressant efficacy with the restoration of neuroplasticity in depression pathophysiology[102,103].

ANTIDEPRESSANT DRUGS AND NEUROGENESIS

Neurogenesis refers to the self-repair or functional reconstruction process of the nervous system after damage, encompassing the regeneration of neurons (nerve cells), regrowth of axons (nerve fibers), and re-establishment of synaptic connections. In patients with MDD, neurogenic capacity is typically suppressed, particularly in key brain regions such as the hippocampus and prefrontal cortex. Convergent evidence indicates that MDD is closely correlated with reduced neuroplasticity, neuronal atrophy, and diminished neurogenesis (formation of new neurons)[104].

Neuroimaging studies have revealed reduced cerebral blood flow, decreased metabolic activity, and diminished volumes in the limbic system, hippocampus, prefrontal cortex, and amygdala among patients with MDD[105-109]. Numerous studies have consistently demonstrated a reduction in hippocampal volume in MDD[110-113]. Antidepressant drugs, such as fluoxetine, have been demonstrated to reverse or prevent this hippocampal atrophy in patients with MDD[114,115]. Stockmeier et al[116] reported increased neuronal and glial cell density in the dentate gyrus and cornuammonis regions of the hippocampus in patients with MDD. The observed hippocampal volume reduction in depression may contribute to this elevated cellular packing density within hippocampal structures.

In adult mammalian brains, neural stem cell populations are primarily located in the hippocampal dentate gyrus, ventricular and subventricular zones, as well as the region connecting the lateral ventricles to the olfactory bulb. Neural stem cells can be isolated from both the dentate gyrus of the hippocampus and the lateral walls of the ventricular system in adult mammals. The cells in the ventricular zone and subventricular zone of the lateral ventricle walls generate neural progenitor cells that migrate to the olfactory bulb. In contrast, neural stem cells originating from the subgranular zone of the dentate gyrus migrate into the granule cell layer[117]. The hippocampus serves as a central hub for emotional integration and higher cognitive functions. Newborn neurons undergo proliferation, migration, and differentiation, ultimately forming synaptic connections with surrounding neurons. The rate of new neuron formation is closely associated with neurocognitive capabilities. External factors such as environmental enrichment, stress, and glucocorticoids can modulate adult hippocampal neurogenesis[118]. These findings have highlighted neurogenesis and its foundational processes as essential areas of study in the fields of neuroscience and psychiatry[119].

Antidepressant drugs such as fluoxetine[120,121], escitalopram[122], and tianeptine[123] can reverse stress-induced reductions in adult neurogenesis[124,125]. With the exception of one study demonstrating that repetitive transcranial magnetic stimulation fails to counteract the effects of chronic psychological stress on hippocampal neurogenesis[126], all other antidepressant treatments investigated to date have been found to enhance hippocampal neurogenesis and/or reverse stress-induced impairments[127,128]. These findings form the foundation of the neurogenic hypothesis of antidepressant action. Antidepressant-induced neurogenesis requires chronic dosing and is confined to the hippocampus, with unnoticeable changes in proliferation rates in the cerebral cortex. Notably, chronic fluoxetine treatment (a serotonin reuptake inhibitor) fails to stimulate neurogenesis in 5-hydroxytryptamine receptor 1A receptor knockout mice, whereas imipramine (which also inhibits norepinephrine reuptake) retains this capacity[129]. This hypothesis continues to gain substantial support, leading to proposals that: (1) Treatments enhancing neurogenesis may possess antidepressant properties; and (2) Cellular signaling pathways stimulating neurogenesis could represent novel targets for future antidepressant development[130,131]. Riluzole, primarily used to treat amyotrophic lateral sclerosis, inhibits glutamate release and blocks presynaptic calcium and sodium channels. Some studies report that riluzole exhibits antidepressant-like properties while stimulating adult hippocampal neurogenesis[132-134]. The proliferative impact on neural cells is reliant on the BDNF signaling pathway, which is also associated with conventional antidepressant mechanisms[135]. Further supporting the hypothesis that pro-neuroplastic/neurogenic factors may confer antidepressant effects is vascular endothelial growth factor[136-138]. This well-established angiogenic and neurogenic factor demonstrates antidepressant properties in chronic stress animal models[139]. Stress-induced suppression of neurogenesis correlates with reduced vascular endothelial growth factor expression, suggesting its involvement in depression pathophysiology[140,141].

The hippocampus is a key structure for memory processes, and reduced hippocampal neurogenesis may contribute to memory impairments in patients with MDD[142]. Studies report that when adult hippocampal neurogenesis is inhibited, hippocampal-dependent learning and memory functions are impaired[143-146]. In animal models of depression (forced swim test and learned helplessness), decreased proliferation of granule layer precursor cells has been observed, leading to reduced numbers of newborn neurons in the dentate gyrus. Hippocampal volume reduction has also been documented in patients with MDD[147]. Chen et al[148] found that various antidepressants can increase the number of precursor cells in the hippocampal dentate gyrus, leading to a gradual improvement in clinical symptoms. Czéh et al[149] reported that antidepressant treatment can protect against stress-induced hippocampal atrophy.

Malberg et al[150] further demonstrated that repeated courses of antidepressants enhance hippocampal cell proliferation. To quantify this effect, 5-bromo-2’-deoxyuridine (BrdU) was injected following the last treatment, and proliferating cells were identified by immunohistochemistry 24 hours after BrdU administration. The elevated number of BrdU-positive cells at this time point indicates increased cell proliferation. This cell proliferation was observed using multiple classes of antidepressants, including a monoamine oxidase inhibitor (tranylcypromine), a SSRI (fluoxetine), and a selective norepinephrine reuptake inhibitor (reboxetine). It was further demonstrated that long-term (2 weeks), but not short-term (1-5 days), drug administration was necessary for the fluoxetine-induced increase in cell proliferation and neurogenesis. An increased count of BrdU-positive cells was still evident at one month. Most of these cells had become neurons, indicating a net increase in neurogenesis[151]. These findings collectively provide compelling evidence for a close relationship between depression and impaired neurogenesis and defective plasticity. Applying these mechanisms to clinical indications may enhance the long-term remission and functional recovery outcomes of conventional treatments through drugs, behavioral interventions, or neuromodulation therapies that promote neural regeneration.

CONCLUSION

In summary, evidence from molecular, basic, and clinical levels collectively demonstrates that neurotrophic signaling plays a central role in the pathogenesis and treatment of depression. BDNF and GDNF, as key modulators linking stress, synaptic plasticity, and neuronal survival, provide a framework for understanding the unified mechanism of antidepressants. Future research must overcome several limitations, including standardizing peripheral neurotrophic biomarker measurements, further clarifying causal relationships, and conducting clinical validation based on neurotrophic factors. With advances in gene regulation, neuroimaging, and personalized medicine, strategies targeting neurotrophic signaling hold promise for translating mechanistic research into precise clinical interventions.

MDD is a complex disorder involving multiple neurotransmitters and brain regions. Earlier studies into antidepressants concentrated on their influence on brain neurotransmitters. However, more recent research has focused on investigating how these drugs impact intracellular signaling pathways and the growth of neurons in neural cells. The primary role of the nervous system is to store and process information, a task that cannot be achieved by individual neurons or synapses alone. Alternatively, it is accomplished through dynamic neural networks, which are created by interconnected neurons. In patients with MDD, alterations may occur in the stability and functionality of these neural networks, extending beyond mere chemical imbalances. Antidepressants have neurotrophic effects that can enhance synaptic connections and stimulate the growth of new neurons, thus helping restore the function of neural networks. Synaptic and neurogenic enhancements induced by antidepressants require time to manifest and develop. This explains the typical 2-3 weeks delay in clinical efficacy. By identifying key neural networks and characterizing their neurobiology, clinicians can optimize combinations of pharmacological and non-pharmacological treatments. These advances may yield more effective and safer antidepressants and improve the use of existing medications for patients with MDD.

ACKNOWLEDGEMENTS

We are grateful to all the psychiatrists and nurses who participated in our current study.