اثربخشی پرگابالین در نشانه های افسردگی در ارتباط با اختلال اضطراب فراگیر: تجزیه و تحلیل تجمعی 6 مطالعه انجام شده

Epidemiological evidence supports comorbidity of generalized anxiety disorder (GAD) and major depressive disorder (MDD) or dysthymia, and its association with significant disability. As pregabalin, a new α2-δ anxiolytic treatment for GAD, unlike most other licensed treatments for GAD has not undergone investigation in patients with MDD, we examined its efficacy in depressive symptoms associated with GAD, through a post-hoc analysis of the existing clinical trial database. The results provide consistent evidence that in patients with GAD pregabalin reduced associated symptoms of depression. This was seen in the 150 mg/day, 300–450 mg/day and 600 mg/day dosing groups. Even in subjects with more prominent depressive symptoms, pregabalin remained effective for both sub-syndromal depression and GAD symptoms, with pregabalin 300–450 mg/day demonstrating the most beneficial response. In conclusion, pregabalin, an alternative treatment option for GAD with a novel mechanism of action, also demonstrated efficacy in treating depressive symptoms typically encountered in GAD patients.

Recent epidemiological data provide evidence on the comorbidity of generalized anxiety disorder (GAD) and major depressive disorder (MDD) or dysthymia. In the US National Comorbidity Survey Replication—NCSR (Kessler et al., 2005), the 12-month prevalence of GAD assessed in a nationally representative face-to-face household survey in 9282 respondents using a fully structured diagnostic interview was 3.1%, with 77.5% of GAD cases of a moderate or serious severity. This study also found statistically significant correlations between GAD and Major Depressive Disorder (0.62, p < 0.05) or dysthymia (0.55, p < 0.05). The European Study of the Epidemiology of Mental Disorders ( Alonso et al., 2004) examined 12-month comorbidity patterns of mood and anxiety disorders in 21,425 completed computer-assisted diagnostic interviews. Among subjects with GAD, 69.4% also fulfilled the diagnostic criteria for at least one other disorder during the previous 12-months, with females having significantly higher comorbidity (75.7%, 95% CI 66.9, 84.6) than males (51.6%, 95% CI 32.4, 70.8). GAD had strong associations with MDD (OR 33.7, 95% CI 23.2, 49.1) and dysthymia (OR 17.6, 95% CI 10.4, 29.7), and these associations were again particularly pronounced in women. Prevalence rates of GAD in primary care samples were found to vary between 2.8% and 8.5% ( Roy-Byrne and Wagner, 2004, Kroenke et al., 2007 and Ansseau et al., 2005), and of comorbid GAD plus MDD were 4.1% ( Ansseau et al., 2005). A recent epidemiological study of the prevalence of GAD among primary care patients in Denmark, Finland, Norway, and Sweden found that the age-standardized rates ranged from 4.1–6.0% for males and from 3.7–7.1% for females ( Munk-Jørgensen et al., 2006). The presence of comorbid MDD in GAD subjects is associated with significant disability (Hunt et al., 2002 and Wittchen, 2004). The disability associated with GAD comorbid with MDD was greater than that when GAD was comorbid with other disorders (Hunt et al., 2004). In addition, comorbidity with MDD significantly lowered the likelihood of recovery from GAD while increasing the likelihood of its recurrence (Bruce et al., 2001). The presence of comorbid mood disorder in subjects with GAD was associated with a more chronic course of illness, a poorer outcome and a higher incidence of relapse and suicide (Fawcett, 1990 and Clayton et al., 1991). GAD with comorbid mood symptoms may also be associated with a lower response to pharmacological treatment (Silverstone and Salinas, 2001). In addition, both minor depressive disorder and sub-syndromal depressive symptomatology were found to be highly prevalent in subjects with GAD and associated with significant functional impairment (Rapaport and Judd, 1998 and Rapaport et al., 2002). Current clinical management of GAD usually involves pharmacotherapy, psychotherapeutic interventions, or their combination (Hidalgo and Davidson, 2001). Historically, benzodiazepines have been the preferred pharmacologic intervention for GAD, however their use is associated with drowsiness/sedation, potential for abuse and dependence and lack of efficacy in depressive symptoms associated with GAD (Montgomery, 2006). Current treatment guidelines for GAD emphasize the role of selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SSNRIs), tricyclic antidepressants (TCAs), and the 5-HT1A agonist buspirone, rather than benzodiazepine anxiolytics (Bandelow et al., 2002 and Baldwin et al., 2005). It is thought that the ideal treatment for GAD would provide relief from both GAD and the comorbid condition, thus reducing the need for polypharmacy (Nutt et al., 2002). Pregabalin, the first agent in the new class of α2-δ anxiolytic drugs, is a new treatment for GAD. Unlike other anxiolytics, it binds with high specificity to the α2-δ subunit of P/Q-type voltage-gated Ca++ channels (Dooley et al., 2002 and Fink et al., 2002), thereby reducing the influx of Ca++ at nerve endings and attenuating the release of excitatory neurotransmitters such as norepinephrine, glutamate, aspartate, substance P, and calcitonin gene-related peptide (Fehrenbacher et al., 2003, Field et al., 2001, Maneuf and McKnight, 2001, Dooley et al., 2000a and Dooley et al., 2000b). Pregabalin has no activity at GABA-A, GABA-B, or benzodiazepine receptors, and unlike SSRIs and SNRIs, does not bind to pre- or post-synaptic serotonin receptors, nor does it inhibit reuptake of serotonin or norepinephrine. Currently there is no data demonstrating activity of pregabalin in animal models of depression. Across the dosing range of 150–600 mg/day, pregabalin has a linear pharmacokinetic profile with predictable oral absorption and ≥ 90% bioavailability. In addition, it does not bind to plasma proteins, is not hepatically metabolized, is excreted virtually unchanged by the kidney, and consequently has a low potential for drug–drug interactions (Lyrica prescribing information). The efficacy, tolerability, and safety of pregabalin in GAD were assessed in 6 placebo-controlled, double-blind studies of comparable design, summarized in Table 1. In addition to efficacy in GAD, pregabalin has demonstrated efficacy in the treatment of neuropathic pain syndromes such as diabetic peripheral neuropathy (Freyhagen et al., 2005, Richter et al., 2005, Lesser et al., 2004 and Rosenstock et al., 2004), postherpetic neuralgia (Van Seventer et al., 2006, Sabatowski et al., 2004 and Dworkin et al., 2003), central neuropathic pain (Siddall et al., 2006) and fibromyalgia syndrome (Crofford et al., 2005). It is approved as an add-on treatment for partial seizures with or without generalization in adults, peripheral and central neuropathic pains, and generalized anxiety disorder in Europe; whereas in the United States, it is approved as an add-on treatment for partial seizures with or without generalization in adults, neuropathic pain in diabetic peripheral neuropathy and postherpetic neuralgia, and fibromyalgia.