human psychopharmacology

Hum. Psychopharmacol Clin Exp 2010; 25: 1729. Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hup.1074

REVIEW ARTICLE

Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efcacy
Bernardo DellOsso1*, Massimiliano Buoli1, David S. Baldwin2 and A. Carlo Altamura1
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Department of Psychiatry, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via F. Sforza 35, Milano, Italy 2 Clinical Neuroscience Division, School of Medicine, University of Southampton, UK

Anxiety disorders are common psychiatric conditions that typically require long-term treatment. This review summarizes current knowledge of the pharmacological treatment of anxiety disorders with serotonin norepinephrine reuptake inhibitors (SNRIs) with specic emphasis on the ndings of recent randomized clinical trials and relevant neurobiological investigations. It is now well established that gabaergic, noradrenergic and serotonergic systems play a critical role in the pathophysiology of anxiety disorders, abnormalities in these systems being related to structural and functional alterations in specic brain areas such as the amygdala, prefrontal cortex, locus coeruleus and hippocampus, as repeatedly shown by neuroimaging studies. SNRIs selectively inhibit norepinephrine and serotonin reuptake and have shown to be efcacious and generally well tolerated treatments in patients with anxiety disorders, with some potential clinical advantages over selective serotonin reuptake inhibitors (SSRIs), which are considered by many to represent rst-line pharmacological treatments in patients with anxiety disorders. Anxiety disorders are characterized by a typically chronic course, high rates of comorbidity and frequent partial response to standard treatments, and the increasing use of SNRIs reects currently unmet clinical need, in terms of overall response, remission rates and treatment tolerability. Copyright # 2009 John Wiley & Sons, Ltd. key words serotonin norepinephrine reuptake inhibitors (SNRIs); anxiety disorders (ADs); selective serotonin reuptake inhibitors (SSRIs)

INTRODUCTION Epidemiologic data and general clinical aspects of ADs Anxiety disorders are the most common mental disorders and are characterized by the presence of impairing anxiety symptoms that vary widely in terms of their nature, severity, frequency, persistence and consequences. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IVTR, American Psychiatric Association, 2000), this group of disorders includes panic disorder (PD), generalized anxiety disorder (GAD), specic (simple) phobia, social anxiety disorder (SAD, also known as social phobia), post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD). The anxiety disorders are extremely prevalent conditions, with a lifetime prevalence in Europe of
* Correspondence to: B. DellOsso, Department of Psychiatry, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via F. Sforza 35, 20122, Milano, Italy. Fax: 39-0250320310. E-mail: bernardo.dellosso@mssm.edu

approximately 13.621% in the general population (Alonso et al., 2004; Wittchen and Jacobi, 2005). According to the Epidemiologic Catchment Area (ECA) study, 6% of men and 13% of women in the United States full criteria for an anxiety disorder in a 6-month observation period (Leon et al., 1995). The lifetime prevalence of individual disorders varies widelyPD, 1.53.5%; SAD, 2.413.3%; GAD, 4.16.6%; PTSD, 1.37% and OCD, 0.78.0% (Fontenelle et al., 2006; Keane et al., 2006; Kessler et al., 1994; Lepine, 2002; Lieb et al., 2005; Perkonigg et al., 2000; Wittchen and Hoyer, 2001). It is difcult to provide reliable prevalence rates for specic phobia, as the majority of affected patients do not present with these problems to health care services; however, in the National Comorbidity Study, almost 50% of respondents reported a lifetime occurrence of an unreasonably strong fear of one or more phobic stimuli (Kessler et al., 1994). Taken together, these prevalence data demonstrate that anxiety disorders represent one of the most prevalent and disabling groups of mental disorders, with a substantial social and economic
Received 22 December 2008 Accepted 2 September 2009

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impact on affected people, their families and wider society (Kroenke et al., 2007). There is a considerable degree of overlap between anxiety disorders (Body et al., 1984; Kessler et al., 1994), the occurrence of one disorder increasing the probability of having another. Approximately 75% of patients with an anxiety disorder will also meet diagnostic criteria for at least another psychiatric condition (De Girolamo et al., 2006). In the large majority of patients affected by co-morbid disorders in which one condition is anxiety disorder, there is good evidence that the anxiety disorder usually appears rst (Kessler et al., 1996; Regier et al., 1998). Although there are important differences in the clinical course of the various anxiety disorders (Yonkers et al., 2003), most are long-term conditions with either an episodic course, with alternating phases of ill-health and relative well-being, or chronic conditions waxing and waning in severity but without full remission of symptoms. The aims of treatment, therefore, are both the resolution of acute symptoms and the prevention of relapse (Angst et al., 2009). However, despite the high prevalence, morbidity, comorbidity and chronic course, fewer than 30% of affected patients in Europe present with anxiety symptoms to healthcare services (Alonso et al., 2007), and furthermore even fewer patients receive evidence-based treatment. Unmet clinical needs in the pharmacological treatment of ADs Several characteristics are required for an optimal anxiolytic treatment, including its effectiveness across a wide range of anxiety symptoms, the capacity to achieve remission and prevent future recurrences, and a favourable tolerability prole in terms of few side effects, few interactions and no discontinuation symptoms (Baldwin, 2006). Although effective in reducing anxiety symptoms in some patients, tricyclic antidepressants are not recommended in long-term treatment, being associated with more side effects when compared to selective serotonin reuptake inhibitors (SSRIs) (Hirschfeld, 2000). In most recent evidence-based guidelines, SSRIs are regarded as the rst-line pharmacological treatment for anxiety disorders (Allgulander et al., 2003; Baldwin et al., 2005; Bandelow et al., 2002; Koran et al., 2007; Ursano et al., 2004). With over 20 years of clinical experience practice and clear evidence of efcacy from randomized placebo-controlled trials, SSRIs have clear advantages over tricyclics and monoamine oxidase inhibitors (MAOIs), at least in
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initial treatment. Nevertheless, many patients undergoing SSRI treatment develop troublesome side effects such as sexual dysfunction (Baldwin, 2004) and weight gain (Papakostas, 2008) and these may represent a major problem in terms of adherence, particularly over long-term treatment. Benzodiazepines are still often used in clinical practice to reduce acute anxiety symptoms but are not recommended for long-term treatment in patients other than those with the most severe and disabling disorders (Argyropoulos and Nutt, 1999; Baldwin et al., 2005). Benzodiazepines may be more effective in relieving somatic symptoms of anxiety than some antidepressant drugs, but less effective in reducing psychological symptoms, and are often associated with side effects such as sedation and cognitive impairment (Shader and Greenblatt, 1993). Another hazard associated with use of benzodiazepines is the development of tolerance, dependence and a withdrawal syndrome, which is more frequent after long times use at higher doses and when the drugs are abruptly discontinued (Shader and Greenblatt, 1993). There is also an increasing body of evidence suggesting that some anticonvulsants, in particular pregabalin, have anxiolytic potential and might therefore be an alternative treatment option in some anxiety syndromes (Baldwin and Ajel, 2007; Mula et al., 2007; Van Ameringen et al., 2004; Zwanzger et al., 2007). The serotonin norepinephrine reuptake inhibitors (SNRIs) are dual action antidepressants that inhibit the reuptake of both serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). SNRIs are a useful alternative to SSRIs and are often used in patients with anxiety disorders, following a partial response or nonresponse to SSRI treatment (Allgulander et al., 2001) (Table 1.). This reviews summarizes the main neurochemical and neuroimaging data related to the pathophysiology of anxiety disorders and the rationale for the use of SNRIs with particular emphasis on their pharmacological properties. The ndings of randomized controlled trials assessing efcacy and tolerability of SNRI treatment are presented and discussed along with consideration of the potential advantages for SNRIs over SSRIs in the treatment of anxiety disorders. NEUROBIOLOGICAL BASES OF ANXIETY DISORDERS Neurochemical aspects of anxiety disorders Investigations have evaluated the role of disturbances of different neurotransmitter systems in the pathogenHum. Psychopharmacol Clin Exp 2010; 25: 1729. DOI: 10.1002/hup

snris in anxiety disorders

Table 1. FDA approved drugs for the treatment of anxiety disorders Panic disorder Benzodiazepines Alprazolam SSRIs Fluoxetine Paroxetine Sertraline Generalized Anxiety Disorder SNRIs Duloxetine Venlafaxine SNRIs Venlafaxine

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SSRIs Paroxetine Sertraline Escitalopram Social Anxiety Disorder

Anticonvulsants Pregabalin

SSRIs Paroxetine Sertraline Post-Traumatic Stress Disorder SSRIs Paroxetine Sertraline Obsessive-Compulsive Disorder Tryciclics Clomipramine SSRIs Fluoxetine Fluvoxamine Sertraline

esis of ADs, in particular in the limbic system, including the amygdala and other structures (Davis, 1997; Garakani et al., 2006; LeDoux, 1998). Research has focused principally on the role of GABAA/BZD complex, the norepinephrine and serotonin systems (Gorman et al., 2002). GABAA receptors are thought to modulate anxiety responses through projections to limbic areas with a resultant decrease in turnover of monoamines, ` and to the locus coeruleus and raphe nuclei with suppression of neuronal ring (Kardos, 1999). In particular, it has been hypothesized that downregulation of the GABAA-benzodiazepine receptor in anxiety disorders would result in a decreased function of endogeneous neurotransmitters and the expression of characteristic symptoms (Argyropoulos and Nutt, 2003). The norepinephric neurons of the locus coeruleus give rise to diffuse projections to the forebrain, and may play a critical role in mediating response to fear, stress and arousal (Bremner et al., 1996). The central effects of norephinephrine are mediated through postsynaptic a1 and b1 receptors and presynaptic a2 receptors which are important in mediating the presynaptic inhibition of norephinephrine release (autoreceptors) and the release of other neurotransmitters, when located on the terminals of nonnoradrenergic neurons. The a2-adrenergic receptor
Copyright # 2009 John Wiley & Sons, Ltd.

antagonist yohimbine increases the ring of noradrenergic cell bodies in the locus coeruleus and induces anxiety, whereas agents that reduce the ring of these neurons, such as the a2 receptor agonist clonidine reduce symptoms of anxiety (Grimsley, 1995). ` Serotonergic neurons located in the raphe nuclei project to large areas of the brain, including the limbic system and hypothalamus and are integrally involved in the mediation of anxiety responses (Ressler and Nemeroff, 2000). Presynaptic 5-HT1 receptors and postsynaptic 5-HT2 receptors are principally involved in the modulation of anxiety (Salzman et al., 1993). Stimulation of terminal 5-HT1 autoreceptors attenuates the release of serotonin at the nerve ending (Stahl, 1998). Studies of the plasma concentrations of serotonin and its metabolites and receptors have suggested a dysfunction of the serotonergic system; for example, levels of 5-HT in the cerebrospinal uid were reported to be low in patients with anxiety disorders (Johnson and Lydiard, 1995) and administration of m-chlorophenylpiperazine, a non-selective 5HT1 and 5HT2 agonist, leads to an increase of hostility and anxiety in patients with GAD (Germine et al., 1992). It has been hypothesized that SSRIs may act through reducing central 5-HT transmission, suggesting there may be a state of increased serotonergic function in anxiety disorders. However, two major serotonergic systemsone originating from ` the medial raphe nuclei, the other from the dorsal raphe nucleihave been implicated in anxiety, it being hypothesized that each system mediates different aspects of anxiety, and that dysfunction of one or both of these systems would result in differing forms of anxiety disorders (Deakin and Graeff, 1991; Bell and Nutt, 1998). While gabaergic, noradrenergic and serotonergic systems still represent the main focus of attention in relation to the pathophysiology of ADs and to the mechanism of action of different anxiolytic treatments, researchers are moving their efforts to assess the importance of the balance between these systems and of other transmitters and modulators. Structural bases of anxiety and neuroimaging data in ADs Functional imaging techniques have been used intensively to identify possible neurobiological correlates between core anxiety symptoms and anatomical and neurophysiological alterations in the central nervous system (Kilts, 2003). Robust evidence indicates that the amygdala mediates states of
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increased arousal and fear responses (Ohman, 2005). The central nucleus of the amygdala receives information from the visual, auditory, olfactory, nocioceptive and visceral pathways, and mediates the integration of information and execution of autonomic and behavioural fear responses (Kalin et al., 2004). Two types of fear responses have been described: a rapid, less nely tuned mode, in response to immediate threats and activated by a direct pathway from the sensory thalamus to the amygdala, and a slower one that is activated by a thalamo-corticoamygdalo circuit and which allows valuable cortical assessments of threat-related information (Kalin et al., 2004). The prefrontal cortex and the hippocampus are two other key brain structures known to be important in the pathophysiology of anxiety disorders (Shin et al., 2006). The hippocampus is considered to have a role in the processing of contextual information, differentiating between safe versus potentially dangerous contexts; hippocampal dysfunction, consequently, may produce an anxiety response to innocuous stimuli with an overestimation of potentially threatening contexts (Shin et al., 2006). The medial prefrontal cortex may play a critical role in the process of extinction, dened as the reduction of conditioned fear responses when a tone is repeatedly presented without a shock previously associated with the tone (Milad and Quirk, 2002). In animal models, individuals with dysfunctions in the medial prefrontal cortex seem to have difculties in memorizing previous associations between potentially threatening stimuli and lack of shock (Tamminga, 2006). Structural and functional imaging studies have highlighted the role of different brain areas such as the temporal lobe, prefrontal cortex, insula and motor striatal regions in the neural circuitry of PD (Graeff and Del-Ben, 2008). The most consistent ndings suggest: (1) the presence of a left-to-right asymmetry in hippocampal metabolism; (2) hypometabolism in parieto-tempopral areas which may rectify on treatment and (3) changes in anterior cingulate or orbitofrontal metabolism (Malizia, 2003). Studies in patients with PTSD suggest a hyperresponsivity of the amygdala and decient activation of the ventral/medial prefrontal cortex and hippocampus (Liberzon and Sripada, 2008). Structural imaging studies have reported smaller volumes of ventral/ medial prefrontal cortex and hippocampus in patients with PTSD, when compared to healthy controls (Karl et al., 2006). In SAD, functional neuroimaging studies have shown that patients differ from normal controls in
Copyright # 2009 John Wiley & Sons, Ltd.

the processing of social threat-related stimuli and conditioned aversive stimuli (Malizia, 2003); in particular, fMRI studies have shown the involvement of both the amygdala and hippocampus (Etkin and Wager, 2007). In OCD, obsessions have been associated with overactivity of the frontal cortex, possibly as a consequence of impaired thalamic gating, attributable in turn to decient striatal function; by contrast, compulsions may be the result of aberrant striatal activity (Saxena and Rauch, 2000). Resting state PET and SPECT studies in patients with OCD showed increased activity in the orbifrontal cortex and striatum, when compared to healthy controls (Whiteside et al., 2004). An fMRI study has found a signicant correlation between anxiety and degree of activation of the amygdala (Mataix-Cols et al., 2003). In patients with GAD, a PET study found metabolic differences in occipital lobe, limbic regions and basal ganglia in GAD, when compared to healthy controls, after benzodiazepine treatment (Wu et al., 1991). More recently, an fMRI study found that individual differences in the degree of rostral anterior cingulate cortex and amygdala activation predicted better treatment outcomes to venlafaxine (Whalen et al., 2008). Taken together, these neuroimaging ndings have led some to hypothesize a potential neurobiological classication of the anxiety disorders, based on predominant involvement of the amygdala (SAD), the combination of amygdala and cortical involvement (PTSD and PD), or on predominant involvement of cortico-striatal systems; however, there is at present insufcient consistent evidence to categorize GAD and OCD according to this scheme (Cannistraro and Rauch, 2003). Nevertheless, scientic advances in neurobiology are progressively elucidating fundamental brain mechanisms and the areas underlying anxiety, and this should eventually provide a rational base for pharmacological treatment in anxiety disorders. Detailed description of the genetic bases of anxiety disorders is beyond the scope of this review, but a robust body of evidence from family, twin and adoptee studies indicates a complex genetic component is involved in the development of anxiety-related traits (Hettema et al., 2001). For example, allelic variation of 5-HT transporter expression and function, in particular, seems to play a crucial role in the vulnerability to anxiety disorders. In addition, a specic association of the 5-HT transporter polymorphism and amygdala activation is supported by the ndings of a recent meta` analysis (Munafo et al., 2008).
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snris in anxiety disorders

Table 2. Pharmacokinetics of SNRIs Venlafaxine IR/SR Therapeutic dose range 75225 (divided dose IR) (mg/day) (single dose SR) Bioavailability 45% Biotransformation pathways CYP2D6 and others Major metabolites O-desmethyl-venlafaxine (ODV) (active) Half-life Elimination routes Protein binding NE/5-HT afnity ratio 4 h (parent) Urine (87%) 27% (parent) 15.7 Desvenlafaxine (ODV) 50 Duloxetine Milnacipran

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60120 (with a maximum 25200 of 60 mg each dose) 80.5% 50% (reduced of a third in smokers) 85% CYP3A4 (minimal) CYP2D6 and CYP1A2. CYP2D6 or CYP2C19 No active metabolites 4-hydroxy duloxetine No active metabolites glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate (no active) 10 h 12 h (parent) 12 h (parent) Urine unchanged, heces Urine unchanged (<1%), Urine unchanged metabolites urine metabolites (about 70%), (50%), urine conjugated (30%), heces metabolites (about 20%) urine oxidized (20%) 30% >90% (parent) 13% (parent) 13.8 9.3 2

MECHANISM OF ACTION OF SNRIs SNRIs bind to 5-HT and norepinephrine transporters to selectively inhibit the reuptake of these neurotransmitters from the synaptic clefts, and therefore have a dual mode of action to increase the availability of 5-HT and norepinephrine within the central nervous system. The rationale for use of SNRIs comes from the possibility to correct dysfunctions of central serotonergic and noradrenergic functions which are thought to play a critical role in the pathophysiology of anxiety disorders. In addition, SNRIs have the advantage to act simultaneously on different areas of functioning that some authors ascribe to particular monoamines (for example, aggression to 5-HT, and decits in motivation to norepinephrine) (Healy and McMonagle, 1997; Stahl, 1999). The class of SNRIs currently includes the following agents: venlafaxine and its active metabolite drug desvenlafaxine, duloxetine and milnacipran (Table 2).

Venlafaxine

reached within 4 days of treatment. Renal elimination is the primary route of excretion. Both venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV) have linear kinetics. Venlafaxine is available in both immediate-release (IR) and extended release (XR) formulations: the extended release formulation simplies administration, as once-daily dosing achieves similar bioavailability to that with the twice-daily dose. The starting dose is generally 75 mg/day and the recommended maximum dose is 375 mg/day. Reduced doses are recommended in patients with hepatic cirrhosis and severe renal disease. In healthy elderly patients, however, dose adjustments may not be necessary (Kent, 2000). Both venlafaxine and its metabolites have little afnity for muscarinic, cholinergic, H1-histaminic or a-adrenergic receptors, and have no monoamine oxidase A or B inhibitory activity (Kent, 2000). Venlafaxine is though to act primarily as an SSRI at low therapeutic dosages (<100 mg/day), only becoming a dual reuptake inhibitor as the dosage increases (Kelsey, 1996; Roseboom and Kalin, 2000). Desvenlafaxine

Venlafaxine was the rst SNRI to be introduced. It is a bicyclic phenylethylamine compound (Thase and Sloan, 2006). After oral administration Venlafaxine is well absorbed from the gastrointestinal tract and undergoes extensive hepatic rst-pass metabolism. Peak plasma concentrations are achieved within 2 h of oral intake and steady-state plasma concentrations are
Copyright # 2009 John Wiley & Sons, Ltd.

Desvenlafaxine is the only major active metabolite of venlafaxine and like the parent compound is well absorbed after oral administration (80% bioavailability) with a half-life of approximately 910 h. The time
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to maximum concentration is 7.5 h, and steady-state concentrations of desvenlafaxine are reached within 3 4 days of treatment. The compound has low protein binding, independent of its concentration. The recommended dose of desvenlafaxine is 50 mg/day, without regard to meals. Elimination occurs in the form of a glucuronide conjugate metabolite, with a low possibility of drug interactions (Septien-Velez et al., 2007). In addition, the inhibition of CYP450 enzymes by the agent is minimal (Shilling et al., 2005). Desvenlafaxine has a NE/5-HT afnity ratio of 13.8 (Roseboom and Kalin, 2000), and when compared to VEN its norepinephrine-binding afnity is almost three times higher (Sopko et al., 2008). The main pharmacokinetic difference between desvenlafaxine and its parent drug is the route of metabolism: whereas venlafaxine is metabolized primarily by CYP2D6, desvenlafaxine is conjugated via uridine diphosphate glucuronyl transferase (UGT), and therefore there may be more potential drug interactions for venlafaxine than desvenlafaxine during concomitant administration with other medications that affect the CYP2D6 pathway (Sopko et al., 2008). 3.3 Duloxetine

NE with Kis of 0.8 nM and 7.5 nM, respectively (having a NE/5-HT afnity ratio of 9:3) (Barkin and Barkin, 2005). Milnacipran

Milnacipran shows linear pharmacokinetics over a dose range of 25200 mg/day. It is rapidly and extensively absorbed (>85%) and has a half-life of 12 h with steady-state reached within 48 h when administrated twice a day (Delini-Stula, 2000). Milnacipran is not metabolized by cytocrome P450 and is eliminated by renal excretion (Preskorn, 2004); as a consequence, clearance is signicantly prolonged in patients with renal failure, with a half-life three times longer than in normal volunteers (Puozzo et al., 1998b). By contrast its pharmacokinetic properties are essentially unchanged in patients with severe liver impairment (Puozzo et al., 1998a). Plasma protein binding is low and non-saturable. None of its metabolites have meaningful pharmacological activity at clinical levels. The NE/5-HT afnity ratio of milnacipran is 2:1 (Puozzo et al., 2002), this being the closest to a 1:1 ratio of all the SNRIs. RANDOMIZED CONTROLLED TRIALS AND OPEN STUDIES WITH SNRIs IN ANXIETY DISORDERS

Duloxetine shows linear kinetics at the therapeutic dosage (60120 mg/day). The mean elimination halflife is 12.5 h and steady concentration is reached within 3 days at each dose (Hunziker et al., 2005). Duloxetine undergoes phase I oxidation carried out by cytochrome P450 isozymes CYP2D6 and CYP1A2; oxidized duloxetine is then conjugated with glucuronic acid. The primary metabolite observed in plasma is the glucuronide conjugate of 4-hydroxy duloxetine. Intermediate unconjugated metabolites are not detectable in signicant levels in plasma so that conjugation of oxidized duloxetine must occur rapidly. The conjugated metabolites have low afnity for the 5HT, NE or dopamine transporter and are considered to be inactive (Kuo et al., 2004). Elimination is primarily renal, with 72% excreted in the urine and 19% in faeces, the latter resulting from biliary excretion (Lantz et al., 2003). Duloxetine inhibits the uptake of 5HT and
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Panic disorder Two early open-label case series provided preliminary indications of the efcacy of venlafaxine in the treatment of PD even at low dosages (37.5 to 75 mg/ day) (Geracioti, 1995; Papp et al., 1998). A subsequent double-blind placebo-controlled study of 8 weeks in a sample of 25 patients found more certain evidence of efcacy (Pollack et al., 1996). Although one placebocontrolled investigation found rather mixed evidence of efcacy (Bradwejn et al. 2005), a later study found that venlafaxine (225 mg/day) had statistically superior response and remission rates versus placebo, good overall tolerability and similar efcacy to the SSRI paroxetine (40 mg/day) in short-term treatment in a 12-week study involving 664 patients (Pollack et al., 2007). Venlafaxine also has long-term efcacy and a 26-week double-blind placebo-controlled relapse preHum. Psychopharmacol Clin Exp 2010; 25: 1729. DOI: 10.1002/hup

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vention study in patients who had previously responded to open treatment found signicantly fewer relapses during continuation treatment with venlafaxine (Ferguson et al., 2007). There is only limited data for the efcacy of other SNRIs in PD. A single case report describes successful treatment with duloxetine 60 mg/day (Crippa and Zuardi, 2006), and a 10-week open-label study in 31 patients found milnacipran to be effective at doses of 50100 mg/day, 58% of the sample achieving symptomatic remission (Blaya et al., 2007).

signicant improvement in anxiety (Gama et al., 2006). Social Anxiety Disorder (SAD) An early 15-week open-label study suggested the efcacy of exible doses of venlafaxine (112.5 187.5 mg/day) in patients who had not responded to SSRI treatment (Altamura et al., 1999). A subsequent multicentre randomized, double-blind, placebo-controlled, parallel group study found that venlafaxine-XR (75225 mg/day) had signicant superiority over placebo in the short-term treatment, with efcacy and tolerability similar to that of paroxetine (2050 mg/day) (Liebowitz et al., 2005a). Further double-blind placebo controlled trials have conrmed the efcacy of venlafaxine-XR (75225 mg/ day) in both short- and long-term treatment (Allgulander et al., 2004; Davidson, 2003; Liebowitz et al., 2005b; Rickels et al., 2004; Stein et al., 2005). As in most other anxiety disorders, the data for other SNRIs in SAD is limited. A small case series described the successful acute treatment of two patients with duloxetine at the dosage of 120 mg/day (Crippa et al., 2007), and 12 weeks of treatment with milnacipran was benecial in six out of 11 patients with TaijinKyofusho (a form of social phobia common in Japan) (Nagata et al., 2003). Post-traumatic Stress Disorder (PTSD) An open case series of patients with PTSD and depressive symptoms, treated with venlafaxine for 6 weeks reported a signicant reduction in symptom severity and improvement in global functioning (Smajkic et al., 2001). More recently, a 6-month double-blind placebo-controlled study showed that exible doses of venlafaxine-XR (37.5300 mg/day) were effective and generally well-tolerated (Davidson et al., 2006a). A parallel 12-week, multicentre, doubleblind, placebo-controlled study suggested that venlafaxine (37.5300mg/day) was superior to placebo in improving PTSD symptoms, whereas sertraline (25 200 mg/day) was not (Davidson et al., 2006b). Only limited data are available regarding the use of duloxetine in patients with PTSD. Combination of electroconvulsive therapy with both duloxetine and olanzapine produced full remission in a patient with PTSD and comorbid major depressive disorder (Hanretta and Malek-Ahmadi, 2006). There are as yet no published studies with milnacipran in patients with PTSD.
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Generalized Anxiety Disorder (GAD) Many placebo-controlled studies have demonstrated that venlafaxine-XR is effective in reducing both the somatic and psychological symptoms of GAD at doses of 75225 mg/day (Davidson et al., 1999; Hackett, 2000; Rickels et al., 2000) and in preventing relapses during 6-month double-blind treatment (Allgulander et al., 2001; Gelenberg et al., 2000). Comparisons of the SSRIs paroxetine and escitalopram with venlafaxine did not nd any difference of efcacy in acute treatment of GAD although these trials may have had insufcient power to distinguish reliably between treatments (Bose et al., 2008; Kim et al., 2006). Duloxetine was approved by the FDA (February 2007) and the European Medicine Agency (EMEA) (August 2008) for the treatment of GAD. Double-blind short-term placebo-controlled trials nd consistent evidence of efcacy for duloxetine in acute treatment (Allgulander et al., 2007; Endicott et al., 2007; Hartford et al., 2007; Koponen et al., 2007; Rynn et al., 2008). With the exception of the multicentre trial of Koponen et al. (2007) in which a xed dose was administered, all studies lasted 910 weeks and employed exible doses (60120 mg/die) (Allgulander et al., 2007; Endicott et al., 2007; Rynn et al., 2008). Long-term efcacy was demonstrated through the ndings of a double-blind placebo-controlled relapse prevention study (Davidson et al., 2008). Duloxetine is efcacious in reducing signicant pain symptoms (Russell et al., 2007), and has similar efcacy to venlafaxine in reducing somatic symptoms (Nicolini et al., 2008). For milnacipran, data is only limited. A pre-clinical study suggested that chronic administration of milnacipran at doses of 50100 mg/day/kg had the potential to be benecial in reducing anxiety symptoms (Moojen et al., 2006); and a case series of schizophrenic patients with intense anxiety symptoms, treated with clozapine and milnacipran at a dose of 100 mg/day suggested a
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Obsessive-Compulsive Disorder (OCD) Double-blind comparative studies support the efcacy of venlafaxine in patients with OCD and a previous poor response to SSRI treatment (DellOsso et al., 2006). An open naturalistic study of 39 patients with OCD (29 being regarded as treatment-resistant) found that venlafaxine was effective (Hollander et al., 2003). A 12-week randomized double-blind comparative study found that venlafaxine was equally effective to paroxetine in treating OCD (Denys et al., 2003). A previous study, however, did not support the efcacy of venlafaxine in OCD (Yariyura-Tobias and Neziroglu, 1996). No randomized placebo-controlled studies of duloxetine in patients with OCD have yet been published, although it may be helpful in treatment-resistant patients, as suggested in a recent case-series of OCD patients with comorbid mood/anxiety disorders who had not responded to previous treatment with serotonin reuptake inhibitors (SRIs) at adequate doses for at least 12 weeks, (DellOsso et al., 2008). A pre-clinical study with milnacipran, administered at dosages >10 mg/ day, showed inhibition of marble burying behaviour in mice (an animal model of OCD), suggesting potential efcacy in OCD treatment (Sugimoto et al., 2007). We are not aware of any studies evaluating the use of desvenlafaxine in patients with anxiety disorders. Preliminary data suggest some efcacy of this molecule in reducing anxiety symptoms in patients with major depressive disorder (Tourian et al., 2007). SAFETY AND TOLERABILITY DATA Most patients with anxiety disorders will require longterm treatment, particularly those with the most severe symptoms (Kjernisted and Bleau, 2004). However many will stop treatment prematurely due to the onset of side effects (Devane et al., 2005). SSRI treatment generally shows lower rates of treatment discontinuation than with tricyclic antidepressants (McManus et al., 2004), but many patients experience troublesome side effects; indeed, a recent primary care study found that SSRIs were the most frequent class of drug responsible for adverse effects (Gandhi et al., 2003). Two common stated reasons for discontinuation of SSRIs treatment are sexual dysfunction and weight gain; a naturalistic long-term comparison of SSRIs in the treatment of PD found rates of 6.38.2% for weight gain and 515% for sexual dysfunction (Dannon et al., 2007). Venlafaxine may have some advantage over SSRIs in terms of reduced propensity for weight gain (Kim
Copyright # 2009 John Wiley & Sons, Ltd.

et al., 2006), although not for sexual dysfunction (Gregorian et al., 2002). By contrast, elevation of blood pressure is more common in patients treated with venlafaxine when compared to those undergoing SSRI treatment; although a recent naturalistic study in 37 patients treated with high venlafaxine doses (225 525 mg) found a favourable cardiovascular prole (Mbaya et al., 2007). A review of the prevalence of sexual dysfunction with antidepressants suggested that duloxetine was the least likely to provide these side effects (Werneke et al., 2006). Meta-analysis of four double-blind studies found that patients receiving duloxetine (40 120 mg/day) had lower rates of sexual dysfunction during the rst 8 weeks of treatment, when compared to patients receiving paroxetine (20 mg/day) (Delgado et al., 2005). A recent placebo controlled study of duloxetine versus escitalopram in depressed patients found an incidence of treatment-emergent sexual dysfunction of 33.3% for duloxetine, 43.6% for escitalopram and 25.0% for placebo (Clayton et al., 2007). Duloxetine appears to have time-course dependent effect on body weight, with slight weight loss during short-term treatment and subsequent modest weight gain over the long-term (Wise et al., 2006). Data for the other SNRIs is limited. A recent metaanalysis of 16 randomized controlled trials conducted in depressed patients reported that milnacipran showed similar tolerability to other antidepressants in the shortterm, but fewer adverse events and lower premature withdrawal rates (Nakagawa et al., 2008). Milnacipran is associated with the development of sexual dysfunction, although in the majority of patients sexual function improves as depressive symptoms reduce (Baldwin et al., 2008). Considerations of desvenlafaxine are based on its safety prole in depressed patients; in general, the tolerability prole is nearly identical to that of venlafaxine, the most common side-effects being nausea, insomnia, somnolence and dizziness (Sopko et al., 2008). DISCUSSION Anxiety disorders are common conditions associated with a considerable functional impairment (Carpiniello et al., 2002; Demertzis and Craske, 2006). Early diagnosis and long-term treatment are important for improving quality of life of patients as longer duration of untreated illness may be associated with a less favourable course of illness (Altamura et al., 2005, 2008). SSRIs and cognitive-behaviour therapy are held to be the principal treatments for patients with anxiety
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disorders, but cannot be regarded as ideal. A potential advantage for SNRIs is the selective double action on both norepinephrine and serotonin, as this has been found to offer some advantage over conventional SSRI treatment in depressed patients (Silverstone, 2004). Meta-analyses have indicated that treatment of major depressive disorder with venlafaxine achieves greater response and remission rates than is seen with conventional SSRIs (Papakostas et al., 2007; Rudolph, 2002; Smith et al., 2002; Stahl et al., 2002; Thase et al., 2001; Thase, 2008). It is premature to state whether this might also translate into superiority for SNRIs when compared to SSRIs in anxiety disorders (Machado et al., 2006). The relative onset of action of SNRIs and SSRIs in anxiety disorders deserves further research, as at least one placebo-controlled study with venlafaxine in GAD and a placebo-controlled study with duloxetine in depressed patients showed a signicant reduction in anxiety symptoms by the second week of treatment (Allgulander et al., 2001; Detke et al., 2002). Anxiety disorders are often complicated by the presence of comorbid conditions, in particular mood and substance use disorders (Belzer and Schneier, 2004; Brady et al., 2007). Venlafaxine has been found effective in patients with anxiety disorders complicated by other psychiatric conditions (Feighner et al., 1998; Khan et al., 1998; Rudolph et al., 1998), and duloxetine has been found benecial in patients with physical illhealth arising from diabetic neuropathic pain and bromyalgia (Sultan et al., 2008). Furthermore, SNRIs have been usefully combined with atypical antipsychotics in patients with co-morbid mood and anxiety disorders (McIntyre et al., 2007). Another potential advantage for SNRIs over other compounds in the treatment of anxiety disorders may reside in the specic efcacy of these compounds in relieving somatic symptoms which represent a core dimension of many disorders. This effect has been already reported in patients with major depressive disorder and somatic complaints and in patients with anxiety disorders but needs further investigation (Barkin and Barkin, 2005).

approvals for some disorders. In depression, SNRI treatment may combine a shorter latency of onset with higher rates of overall remission than is seen with conventional SSRIs, and may be of particular value in patients with comorbid physical symptoms. These potential advantages cannot yet be regarded as conrmed but even modest differences in efcacy and tolerability for one treatment approach over another may have important public health implications given the high prevalence, disability and chronic nature of these conditions. REFERENCES
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