A 6-week randomized controlled trial with 4-week follow-up of acupuncture combined with paroxetine in patients with major depressive disorder

Abstract

Acupuncture possesses the antidepressant potential. In this 6-week randomized controlled trial with 4-week follow-up, 160 patients with major depressive disorder (MDD) were randomly assigned to paroxetine (PRX) alone (n = 48) or combined with 18 sessions of manual acupuncture (MA, n = 54) or electrical acupuncture (EA, n = 58). Treatment outcomes were measured mainly using the 17-item Hamilton Depression Rating Scale (HAMD-17), Self-rating Depression Scale (SDS), clinical response and remission rates. Average PRX dose taken and proportion of patients who required an increased PRX dose due to symptom aggravation were also obtained. Both additional MA and EA produced a significantly greater reduction from baseline in score on HAMD-17 and SDS at most measure points from week 1 through week 6 compared to PRX alone. The clinical response was markedly greater in MA (69.8%) and EA (69.6%) groups than the group treated with PRX alone (41.7%, P = 0.004). The proportion of patients who required an increase dose of PRX due to symptom aggravation was significantly lower with MA (5.7%) and EA (8.9%) than PRX alone (22.9%, P = 0.019). At 4 weeks follow-up after completion of acupuncture treatment, patients with EA, but not MA, continued to show significantly greater clinical improvement. Incidence of adverse events was not different in the three groups. Our study indicates that acupuncture can accelerate the clinical response to selective serotonin reuptake inhibitors (SSRIs) and prevent the aggravation of depression. Electrical acupuncture may have a long-lasting enhancement of the antidepressant effects (Trial Registration: ChiCTR-TRC-08000278).

Introduction

Depression is a serious mental illness that affects 8–20% of the worldwide population (Ferrari et al., 2012). Although selective serotonin reuptake inhibitors (SSRIs), such as paroxetine (PRX) and fluoxetine (FLX), are a first-line pharmacotherapy for various depressive disorders, there still remains a large portion of depressed patients who do not make a full response and experience relapse and adverse effects of treatment (Arroll et al., 2005). The delay in the onset of the action of SSRIs further prolongs the suffering of patients and exposes them to a substantial risk of suicide (Adell et al., 2005). A high incidence of side effects also has hampered the clinical use of SSRIs (Arroll et al., 2005). These limitations of treatment with SSRIs are thought to be due to the multi-system pathogenesis of depressive disorders (Ward and Irazoqui, 2010). For example, it is well documented that, in addition to a central serotonin (5-HT) deficiency, depressive disorders are associated with hypothalamic–pituitary–adrenal axis dysfunction and abnormalities in the brain regions associated with stress and emotion processing (Rigucci et al., 2010; Ward and Irazoqui, 2010).

As an ancient therapeutic technique, acupuncture has been well confirmed to be a generally safe and well tolerated therapy for neuropsychiatric disorders (He et al., 2012; Lao et al., 2003; Zhang et al., 2010). It has been increasingly introduced into the treatment of various depressive disorders (Manber et al., 2010; Smith et al., 2010; Wu et al., 2012; Zhang et al., 2010). Both manual and electrical acupuncture stimulation considerably enhances the release of 5-HT from the brainstem raphe nuclei, the principal source of 5-HT neuronal bodies sending axons to cortical and subcortical regions (Kwon et al., 2000; Lee et al., 2004; Li et al., 2007; Zhao, 2008). It robustly modulates neuroendocrine functions, in particular the hypothalamic–pituitary–adrenal axis; it reduces stress-induced behavior, and targets brain regions involved in emotion processing (Zhang et al., 2012a). These observations suggest that acupuncture may have an antidepressant potential. Indeed, numerous clinical studies and observations have shown the therapeutic benefits of acupuncture in treating depressed patients (Zhang et al., 2010). Acupuncture is also beneficial in alleviating pain, autonomic, sleep, and other mood symptoms (Zhang et al., 2012a). On the other hand, many studies have shown superior effects of electroacupuncture (EA) compared to manual acupuncture (MA) in alleviating tinnitus (Wang et al., 2010), pain (Sator-Katzenschlager et al., 2003, 2004; Schliessbach et al., 2011; Tsui and Leung, 2002), and modulating rat neuroendocrine function (Feng et al., 2012). Most recently, we have demonstrated that EA has an immediate and short-term effect in enhancing the efficacy in the early phase of FLX treatment of patients with major depressive disorder (MDD) (Zhang et al., 2012b) and potential benefit in patients with postpartum depression (Chung et al., 2012). Hence we hypothesize that adjuvant acupuncture, and in particular EA, may provide a long-lasting enhancement of the antidepressant efficacy of SSRIs.

To test this hypothesis we conducted a 6-week, randomized controlled trial with 4-week follow-up of MA or EA combined with PRX compared to PRX alone in patients with MDD. Adjuvant MA and EA were both studied because a large body of evidence suggests different neural pathways for these two most commonly used stimulation modes (Zhang et al., 2012a). Here, EA is defined as an acupuncture procedure in which inserted needles are manipulated manually at first, followed by electrical stimulation. Paroxetine (PRX) was selected because it is one of the most frequently prescribed SSRIs in China (Fang et al., 2010, 2011) and its pharmacological and therapeutic properties have been well delineated (Gibiino and Serretti, 2012).