Acupuncture for Depression: The Mechanism Underlying Its Therapeutic Effect

Abstract

Background:

Depression is a common psychiatric disorder. Many depressed patients do not respond fully to current medications. Acupuncture has been widely used as an add-on treatment for depression. However, how acupuncture works to produce its antidepressant effect has not been understood fully.

Objective:

This article discusses possible mechanisms underlying the effects of acupuncture in ameliorating depressive symptoms in correlation with theories of depression.

Methods:

PubMed and Google Scholar were used to search for original and review articles with the following keywords: acupuncture AND depression; acupuncture AND monoamine; acupuncture AND BDNF; acupuncture AND inflammation; acupuncture AND cytokine; and stress AND depression.

Results:

Various kinds of evidence showed that acupuncture might be beneficial for treating depression via modulation of the central monoaminergic system, the hypothalmic–pituitary–adrenal axis, brain neurotrophin, and the neuroimmune system.

Conclusion:

Multiple pathways seem to be involved in the mechanism of action of acupuncture, and these mechanisms may work together to produce the antidepressant effects of acupuncture.

Introduction

Depression is one of the most frequent causes of morbidity and mortality,¹ and it has been estimated that ∼10%–15% of the world's population have suffered from this disorder during their lives.² The World Health Organization even ranked depression as the fourth leading cause of disability in the world.³ If not managed well, depression will increase the economic burden on the society indirectly, mainly because of loss of working days and mortality (suicides).⁴

It has been reported that a large portion (50%–60%) of patients with depression do not respond to medication completely.^5,6 A previous study also stated that many patients do not respond fully to first-line antidepressants, selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and fluoxetine.⁷ Moreover, because of the high incidence of adverse effects, the clinical use of these drugs is limited. An evaluation of the use of pharmacotherapy in depression showed that only 7% of patients kept taking antidepressants, while the majority did not continue the medication because of the occurrence of side-effects.⁸ This report indicated that alternative therapies to treat depression in the future are required. Thus, there is an impetus to explore and evaluate nondrug modalities for managing depression.

As an ancient therapy in China, acupuncture has been confirmed to be safe and well-tolerated.⁹ Since being introduced, this therapeutic technique has drawn the attention of the Western countries.¹⁰ During the last 2 decades, there has been a significant rise in the use of complementary medicines such as acupuncture in Western medicine, especially for managing psychiatric disorders.^11,12 A survey in the United Kingdom involving 9408 respondents reported that psychiatric problems, including stress, anxiety and depression, are the second most common reasons for an individual to seek help from an acupuncturist.¹³ A recent systematic review suggested that acupuncture increased the therapeutic efficacy of antidepressants and was proven to be a safe add-on treatment for depression.¹⁴ In this article, the efficacy of acupuncture as a complementary treatment for depression is discussed, including the mechanism underlying the effects of acupuncture for ameliorating depressive symptoms and to what extent acupuncture can be used in the clinic setting as an add-on therapy for depression. Based on current research findings, how acupuncture works in accordance with theories of depression is highlighted.

Methods

A detailed search was performed using PubMed and Google Scholar to identify original and review articles with the following keywords: acupuncture AND depression; acupuncture AND monoamine; acupuncture AND BDNF; acupuncture AND inflammation; acupuncture AND cytokine; and stress AND depression. All appropriate articles with at least an abstract in English were included. Three articles were fully written in Chinese. Therefore, only the English versions of the abstracts were reviewed without retrieving the full texts. The literature was then analyzed and reviewed to figure out the possible working mechanisms of acupuncture on depression treatment.

Results

Based on the already published research articles and systematic reviews, it was found that acupuncture produced antidepressant effects through a variety of mechanisms, including modulation of neurotransmitter signaling, neurotrophin secretion, stress regulation, and immunomodulation. This article presents the possible mechanisms underlying antidepressant effects of acupuncture in accordance with current theories of depression.

The Monoamine Hypothesis of Depression

Monoamines play an important role in regulating mood and cognitive functions. Low levels of monoamine have been associated with various kinds of psychopathologic conditions, particularly mood and anxiety disorders. The most popular theory for depression today is the serotonin/monoamine hypothesis that postulates that depression occurs because of depletion of monoamines in the brain, especially serotonin. The theory was developed in mid-1960s, when the monoamine oxidase inhibitor (MAOI) iproniazid and the tricyclic antidepressant (TCA) imipramine, which increased the level of serotonin and noradrenalin, were shown to improve mood in depressed patients. In addition, administration of dihydrophenylalanine, a precursor of dopamine and noradrenaline, reversed depressive symptoms induced by reserpine, an antihypertension agent that causes depletion of catecholamine.

Later, serotonin was thought to play a more important role in the pathogenesis of depression. This was mainly because catecholamine depletion with normal serotonin neurotransmission did not produce depression, and administration of tryptophan, a serotonin precursor, together with a MAOI potentiated the antidepressant effect, whereas a combination of a MAOI and dopamine did not produce a more therapeutic benefit. However, administration of a 5-hydroxytryptamine (5-HT) synthesis inhibitor blocked the therapeutic effect of a MAOI and a TCA.

Since being introduced in mid-1970s, selective serotonin reuptake inhibitors (SSRIs) have become the most popular drugs for treating depression and the 5-HT hypothesis has dominated the scientific and drug development research in depression.¹⁵

Apart from their success in the pharmaceutical industry, the question of delayed onset of SSRIs in producing therapeutic effects, which require 2–4 weeks, remains unanswered. Several reports suggested that the time-lag effect in SSRI medication is caused by the desensitization of 5-HT autoreceptors that occurs over a 4-week period. Autoreceptors, typically residing in the presynaptic or axonal membrane, are sensitive to the amount of a neurotransmitter in the intercellular fluid. They play a role in feedback function and regulate the inhibitory effect on production and/or release of neurotransmitters. According to this autoreceptor subsensitivity theory, monoamine agonists initially activate the autoreceptors resulting in decreased cell firing. After 2–3 weeks, the autoreceptors become subsensitive because of continuous stimulation and stop sending their inhibitory signal. By this time, the antidepressants will produce their therapeutic effect.¹⁶

Other findings suggest that antidepressant effect is mediated by neurogenesis in the hippocampus, which takes ∼3 weeks to develop. It was demonstrated that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the hippocampal dentate gyrus, suggesting an increase in adult neurogenesis.¹⁷ Interestingly, acute administration of an antidepressant did not result in a similar effect. In humans, antidepressant treatment could enhance proliferation of neural progenitor cells in the hippocampus and reverse hippocampal volumetric loss in patients with depression.¹⁸ The evidence supporting the idea that hippocampal neurogenesis is crucial for mediating the effect of antidepressants was shown by Santarelli and colleagues.¹⁹ In that experiment, antidepressant treatment ameliorated the behavioral symptoms induced by stress in control mice. In contrast, mice who underwent focal X-ray irradiation of the hippocampus to deplete neurogenesis did not respond to either fluoxetine or imipramine.¹⁹ This result suggested that hippocampal neurogenesis is necessary to facilitate the behavioral response of antidepressants, and this might underlie the delayed onset of antidepressant treatment.

Several studies reported that acupuncture can modulate the level of the central monoamine neurotransmitter.^20–23 Acupuncture has been shown to be as effective as embedding thread therapy for treating depression and acupuncture significantly increased levels of norepinephrine, serotonin, and dopamine in the hippocampus and hypothalamus of depressed rats.²⁰ Music electroacupuncture (EA; at ZJ-12H) at Baihui (GV 20) and Yintang significantly increased levels of dopamine, norepinephrine, and serotonin in the frontal lobe and hippocampus, which influenced behavioral response after chronic unpredictable mild stress in rats.²³ In one study, EA stimulation also raised the cerebral level of serotonin in rats.²² An imaging study using functional magnetic resonance imaging (fMRI) showed that acupuncture could activate the median raphe nucleus, which is rich in serotonergic neurons.²⁴

Considering these facts, it is plausible to assume that acupuncture can reduce depressive symptoms by modulating the level of monoamine in the brain. However, there has been no clear evidence suggesting that deficit in monoamine level is the central etiology in depression. Both serotonergic and noradrenergic drugs have been used successfully for treating depression. Even several dopaminergic agents also have shown therapeutic benefits.¹⁵ This reflects the complexity of depression, and, therefore, further research is needed to understand the role of monoaminergic system in depression and how acupuncture treatment can fit into this theory.

The Stress Hypothesis of Depression

The monoamine hypothesis has not provided clear mechanism on the pathogenesis of depression because during the courses of depressive disorders, various kinds of cellular, molecular, structural, and functional alterations are found in the brain.²⁵ One of the major predisposing factors for the development of depression is stress exposure. Either physical or psychosocial stress was associated with the development of depression.^26,27 Stress exposure, such as chronic unpredictable mild stress (CUMS), has been widely used to create animal models of depression. According to the stress hypothesis, alterations in the hypothalamic–pituitary–adrenal (HPA) axis contribute to the development of depression and restoration of HPA axis function is necessary to produce a therapeutic effect.

Chronic stress exposure results in HPA axis hyperactivity, with an increased cortisol level and enlargement of the pituitary and adrenal glands. HPA-axis activation leads to the release of corticotrophin-releasing hormone (CRH) by the hypothalamus, which then stimulates the anterior pituitary gland to secrete adrenocorticotropin hormone (ACTH). ACTH finally stimulates the release of glucocorticoid hormones, mainly cortisol, from the adrenal cortex. Secreted glucocorticoids are able to cross the blood–brain barrier and bind to their receptors in limbic brain areas. Prolonged stress exposure can disrupt the negative feedback mechanism, which is important for inhibiting HPA-axis overstimulation. This disruption is commonly found in depression.

In addition, an excessive cortisol level is neurotoxic and can induce brain damage especially in the hippocampus.¹⁵ Alteration in hippocampal structure is one of the most consistent findings in major depression. Decreased hippocampal volume was found in depressed patients,^28,29 and this was considered to be associated with atrophy of the hippocampal neurons^30,31 and decreased hippocampal neurogenesis.^18,19,29 Reduced neurogenesis induced by stress occurs most prominently in the ventral pole of the hippocampus, which forms a connection to the hypothalamus and the amygdala, two structures responsible for neuroendocrine function and mood regulation. Thus, it is not surprising that hippocampal damage induced by stress results in behavioral changes and mood disorders.²⁶

Previous research using fMRI showed that acupuncture stimulation could modulate the activity of the brain limbic structures. These structures were deactivated during acupuncture and, in particular, the amygdala and hypothalamus responded the most to the treatment. This central effect of acupuncture resulting in suppressing HPA axis hyperactivity might underlie acupuncture's effects in ameliorating depressive symptoms.²⁴ One study reported that acupuncture regulated the stress reaction by modulating expression of glucocorticoids and glucocorticoid receptor (GR) protein. Upregulation of GR protein expression in the hippocampus, hypothalamic paraventricular nucleus, and pituitary gland was observed after EA treatment. This increase of GR protein expression induced feedback inhibition on overexpression of CRH and ACTH receptor due to stress exposure, leading to reduction of GR protein expression in the adrenal cortex and a decreased glucocorticoid level.³² Other studies also revealed that acupuncture ameliorated depressive-like behavior and significantly reduced glucocorticoid levels as well as normalizing HPA abnormality in a mouse model of depression.^33,34 Thus, the effects of acupuncture in modulating the HPA axis might underlie acupuncture's mechanism for treating depression.

The Neurotrophic Hypothesis of Depression

Neurotrophins are a subfamily of neurotrophic factors (NTFs) that regulate many aspects of neuronal development and functions, such as neurogenesis and differentiation, neurite outgrowth, synaptogenesis and synaptic plasticity, and circuit maintenance. The neurotrophins include brain-derived NTF (BDNF), nerve growth factor, neurotrophin-3, and neurotrophin-4. In particular, BDNF is crucial for controlling normal adult brain function and is the major activity-dependent modulator of neuronal and synaptic activity in the brain.³⁵ Among all of the neurotrophins, extensive studies have focused mostly on the association of BDNF and depression.

Impairment of BDNF signaling through its receptor tyrosine kinase receptor B (TrkB) has been implicated in the pathogenesis of mood disorders. According to the neurotrophic hypothesis of depression, decreased expression of BDNF could contribute to the development of depression and upregulation of BDNF expression is involved in the mechanism of action of antidepressant treatment.³⁶ Previous clinical studies reported reduction of BDNF serum levels in depressed patients and that these levels were increased after successful administration of antidepressants.

Postmortem studies also revealed that levels of hippocampal and cortical BDNF were reduced in depressed subjects.³⁷ However, an increased BDNF supply—either through direct injection to the hippocampus³⁸ and midbrain³⁹ or through peripheral administration⁴⁰—produced antidepressant-like effects in rodents. The hippocampus is responsible for spatial memory and mood regulation while the midbrain contains serotonergic neurons that project to the forebrain. Elevation of BDNF mRNA levels and proteins were noticed after chronic treatment with antidepressants, electroconvulsive shock therapy, and physical exercise. In addition, chronic administration of antidepressants also activated TrkB signaling. This indicates that BDNF signaling mediated by TrkB might play a key role in producing the antidepressant-like effects of these drugs.⁴¹

The binding of BDNF to TrkB will activate various intracellular signaling pathways, including mitogen activated protein kinase/extracellular signal-regulated protein kinase and phosphoinositide 3-kinase (PI3K) pathways leading to activation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), a transcription factor that plays a crucial role in neurogenesis and synaptic plasticity and has been reported to be involved in stress response and the development of depression.^42,43

Several studies reported that acupuncture could increase the level of BDNF in the brain. Acupuncture at Baihui (GV 20) and Si shencong (Ex-HN 1) was shown to promote neuronal growth and development, improve neurobehavioral function, and improve learning and memory. Acupuncture at these points also reduced cellular apoptosis and upregulated glial line-derived NTF and BDNF levels in the hippocampus.⁴⁴

EA at Dazhui and Baihui also upregulated expression of BDNF in the ventral midbrain.⁴⁵ Several reports confirmed that acupuncture can increase expression of BDNF via PI3K/Akt [phosphatidylinositol-4,5-bisphosphate 3-kinase] and MEK/ERK1/2 [mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase] signaling pathways by activating TrkB.⁴³ In addition, acupuncture also increased expression of phosphorylated CREB (pCREB) and several extracellular kinases in a mouse model of depression.^46,47 CREB, in its phosphorylated form pCREB, induces BDNF expression leading to neurogenesis, neuronal survival, and neuronal plasticity, which are all implicated in depression. Thus, it is likely that the effect of acupuncture in treating depression is, in part, mediated by acupuncture's action in this pathway.

The Neuroimmune Hypothesis of Depression

Alterations in the immune system have been observed in many cases of depression. Elevated level of proinflammatory cytokines, such as interleukin(IL)–β1, IL-6, and tumor necrosis factor-α (TNF-α), were found in the blood of depressed patients.⁴⁸ It has also been reported that patients treated with cytokines, such as recombinant interferon (IFN), developed symptoms of depression. In addition, depression is more frequently found in people with immune dysfunction–associated diseases. Low dose IL-1 induced development of depressive-like behavior in animals, while administration of cytokine antagonists alleviated the animals' depression symptoms.⁴⁹ This leads to the neuroimmune hypothesis of depression stating that depression is caused by increased production of proinflammatory cytokines, resulting in oxidative and nitrosative brain damage, central monoamine system impairment, and glucocorticoid resistance.²⁵

Oversecretion of proinflammatory cytokines, such as IL-1, TNF-α, and IFN-, significantly altered the release and turnover of monoaminergic transmitters in certain parts of the brain. IL-1 administration reduced the activity of the 5-HT transporter, resulting in a marked decrease of 5-HT in the synapses. Proinflammatory cytokine could also activate the HPA-axis and thus increase corticotropin-releasing factor with a further downstream-signaling cascade, resulting in depression.¹⁵ However, antidepressant treatment has been shown to significantly increase the production of IL-1 receptor antagonist mRNA in rat hippocampus, frontal cortex, hypothalamus, and brainstem. Therefore, it is likely that antidepressants act through inhibition of the IL-1 receptor to counteract the increased production of IL-1.⁵⁰ Given that that the immune system can modulate the monoaminergic system as well as the HPA axis suggest that immune-system dysfunction may play a crucial role in the pathogenesis of depression.

Acupuncture treatment decreased levels of proinflammatory cytokines mRNA and protein expression significantly in the hippocampus, prefrontal cortex, and serum after CUMS in rats and, at the same time, reversed their CUMS-induced depressive-like behavior.⁵¹ A recent clinical trial showed that acupuncture could accelerate the antidepressant effect of SSRIs and significantly reduce the side-effects of these drugs. Acupuncture did not only improve serum 5-HT level more quickly, this treatment also remedied the imbalances of proinflammatory (IL-6) and anti-inflammatory cytokines (IL-4 and IL-10) in depressed patients.⁵² A similar finding was reported when EA was used in a clinical trial.⁵³ These results indicated that acupuncture can modulate the neuroimmune system, which could underlie acupuncture's mechanism of action for treating depression.

Discussion

This review was performed to evaluate the working mechanism of acupuncture for treating depression. Four possible mechanisms are proposed to be responsible for the antidepressant effects of acupuncture including: (1) modulation of the central monoaminergic system; (2) regulation of the HPA axis; (3) modulation of brain neurotrophin; and (4) modulation of the immune system.

The monoamine hypothesis of depression states that depression occurs because of a lack of central monoamines, such as noradrenaline, serotonin, and dopamine. Many studies have shown the effects of acupuncture in modulating the level of these central monoamine neurotransmitters and have suggested that increased monoamine levels were associated with reduced depressive behaviors.^20–24 This raises the possibility that acupuncture may ameliorate depressive symptoms by enhancing neurotransmission mediated by these monoamines, in a manner similar to that of antidepressant drug actions. However, delayed antidepressant effects were observed despite a rapid increase in monoamine levels after antidepressant treatment, suggesting that a more downstream signaling pathway might be involved and that depression might not merely be caused by a monoamine deficit.⁵⁴

An increased level of intrasynaptic monoamine will activate the neurotransmitter receptors, leading to increased cAMP-dependent protein kinase and Ca²⁺ kinases, resulting in activation of CREB. CREB is a transcription factor that regulates the expression of the BDNF gene. Increased CREB and BDNF can provide more trophic support for neurons, enabling them to survive, perform synaptic remodeling, and increase neurogenesis.⁵⁴ Decreased levels of BDNF have been associated with the occurrence of depression symptoms and upregulation of this neurotrophin resulted in amelioration of depressive behavior.^36–43 Evidence has proven that acupuncture could increase CREB-mediated BDNF signaling and thus alleviate depression symptoms.^43–47

Chronic stress exposure has been implicated in the pathogenesis of depression. Prolonged stress disrupts the HPA-axis feedback mechanism and thus maintains a high level of glucocorticoid, which can induce hippocampal damage and depressive-like behavior. Many studies showed that acupuncture could suppress HPA-axis hyperactivity through a central effect on the limbic system, regulation of glucocorticoid receptors, and suppression of cortisol secretion, resulting in improved mood and behavior.^24,32–34

Another mechanism involved in the development of depression is immune system dysfunction. Depression is frequently associated with increased levels of proinflammatory cytokines, ^25,48,49 which induces glucocorticoid resistance, monoamine-system disruption, and oxidative stress in the brain.²⁵ When considering these facts, it is plausible to argue that multiple pathways may underlie the antidepressant effects of acupuncture and it is likely that these mechanisms work in concert to produce these effects.

Conclusions

A series of studies showed that acupuncture could ameliorate symptoms of depression. The mechanism underlying the effects of acupuncture might be the modulation of the central monoaminergic system, the HPA axis, brain neurotrophin, or the immune system. Acupuncture seems to be a promising add-on therapy for depression. However, further research is needed to evaluate its effectiveness.

Footnotes

Author Disclosure Statement

No competing interests exist.

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