Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review...

REVIEW ARTICLE

Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxietydisorders: a comprehensive review of their clinical efficacy

Bernardo Dell’Osso1*, Massimiliano Buoli1, David S. Baldwin2 and A. Carlo Altamura1

1Department of Psychiatry, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena,Via F. Sforza 35, Milano, Italy2Clinical 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 knowledgeof the pharmacological treatment of anxiety disorders with serotonin norepinephrine reuptake inhibitors (SNRIs) with specific emphasis onthe findings 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 beingrelated to structural and functional alterations in specific brain areas such as the amygdala, prefrontal cortex, locus coeruleus andhippocampus, as repeatedly shown by neuroimaging studies. SNRIs selectively inhibit norepinephrine and serotonin reuptake and haveshown to be efficacious and generally well tolerated treatments in patients with anxiety disorders, with some potential clinical advantages overselective serotonin reuptake inhibitors (SSRIs), which are considered by many to represent first-line pharmacological treatments in patientswith anxiety disorders. Anxiety disorders are characterized by a typically chronic course, high rates of comorbidity and frequent partialresponse to standard treatments, and the increasing use of SNRIs reflects currently unmet clinical need, in terms of overall response, remissionrates 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 mentaldisorders and are characterized by the presence ofimpairing anxiety symptoms that vary widely in termsof their nature, severity, frequency, persistence andconsequences. According to the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR, American Psychiatric Association, 2000), thisgroup of disorders includes panic disorder (PD),generalized anxiety disorder (GAD), specific (simple)phobia, social anxiety disorder (SAD, also known associal 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

approximately 13.6–21% 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 theUnited States fulfil criteria for an anxiety disorder in a6-month observation period (Leon et al., 1995). Thelifetime prevalence of individual disorders varieswidely—PD, 1.5–3.5%; SAD, 2.4–13.3%; GAD,4.1–6.6%; PTSD, 1.3–7% and OCD, 0.7–8.0%(Fontenelle et al., 2006; Keane et al., 2006; Kessleret al., 1994; Lepine, 2002; Lieb et al., 2005; Perkonigget al., 2000;Wittchen and Hoyer, 2001). It is difficult toprovide reliable prevalence rates for specific phobia, asthe majority of affected patients do not present withthese problems to health care services; however, in theNational Comorbidity Study, almost 50% of respon-dents reported a lifetime occurrence of an unreason-ably strong fear of one or more phobic stimuli (Kessleret al., 1994). Taken together, these prevalence datademonstrate that anxiety disorders represent one of themost prevalent and disabling groups of mentaldisorders, with a substantial social and economic

human psychopharmacology

Hum. Psychopharmacol Clin Exp 2010; 25: 17–29.

Published online in Wiley InterScience

(www.interscience.wiley.com) DOI: 10.1002/hup.1074

*Correspondence to: B. Dell’Osso, Department of Psychiatry, University ofMilan, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli eRegina Elena, Via F. Sforza 35, 20122, Milano, Italy. Fax: þ39-02-50320310. E-mail: [email protected]

Copyright # 2009 John Wiley & Sons, Ltd.

Received 22 December 2008

Accepted 2 September 2009

impact on affected people, their families and widersociety (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 theprobability of having another. Approximately 75% ofpatients with an anxiety disorder will also meetdiagnostic criteria for at least another psychiatriccondition (De Girolamo et al., 2006). In the largemajority of patients affected by co-morbid disorders inwhich one condition is anxiety disorder, there is goodevidence that the anxiety disorder usually appears first(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 conditionswith either an episodic course, with alternating phasesof ill-health and relative well-being, or chronicconditions waxing and waning in severity but withoutfull remission of symptoms. The aims of treatment,therefore, are both the resolution of acute symptomsand the prevention of relapse (Angst et al., 2009).However, despite the high prevalence, morbidity,comorbidity and chronic course, fewer than 30% ofaffected patients in Europe present with anxietysymptoms to healthcare services (Alonso et al.,2007), and furthermore even fewer patients receiveevidence-based treatment.

Unmet clinical needs in the pharmacologicaltreatment of ADs

Several characteristics are required for an optimalanxiolytic treatment, including its effectiveness acrossa wide range of anxiety symptoms, the capacity toachieve remission and prevent future recurrences, and afavourable tolerability profile in terms of few sideeffects, few interactions and no discontinuationsymptoms (Baldwin, 2006).Although effective in reducing anxiety symptoms in

some patients, tricyclic antidepressants are notrecommended in long-term treatment, being associatedwith more side effects when compared to selectiveserotonin reuptake inhibitors (SSRIs) (Hirschfeld,2000). In most recent evidence-based guidelines,SSRIs are regarded as the first-line pharmacologicaltreatment 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 20years of clinical experience practice and clear evidenceof efficacy from randomized placebo-controlled trials,SSRIs have clear advantages over tricyclics andmonoamine oxidase inhibitors (MAOIs), at least in

initial treatment. Nevertheless, many patients under-going SSRI treatment develop troublesome side effectssuch as sexual dysfunction (Baldwin, 2004) and weightgain (Papakostas, 2008) and these may represent amajor problem in terms of adherence, particularly overlong-term treatment.Benzodiazepines are still often used in clinical

practice to reduce acute anxiety symptoms but are notrecommended for long-term treatment in patients otherthan those with the most severe and disabling disorders(Argyropoulos and Nutt, 1999; Baldwin et al., 2005).Benzodiazepines may be more effective in relievingsomatic symptoms of anxiety than some antidepressantdrugs, but less effective in reducing psychologicalsymptoms, and are often associated with side effectssuch as sedation and cognitive impairment (Shader andGreenblatt, 1993). Another hazard associated with useof benzodiazepines is the development of tolerance,dependence and a withdrawal syndrome, which is morefrequent after long times use at higher doses and whenthe drugs are abruptly discontinued (Shader andGreenblatt, 1993).There is also an increasing body of evidence

suggesting that some anticonvulsants, in particularpregabalin, have anxiolytic potential and might there-fore be an alternative treatment option in some anxietysyndromes (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 thereuptake of both serotonin (5-hydroxytryptamine) andnorepinephrine (noradrenaline). SNRIs are a usefulalternative to SSRIs and are often used in patients withanxiety disorders, following a partial response or non-response to SSRI treatment (Allgulander et al., 2001)(Table 1.). This reviews summarizes the mainneurochemical and neuroimaging data related to thepathophysiology of anxiety disorders and the rationalefor the use of SNRIs with particular emphasis ontheir pharmacological properties. The findings ofrandomized controlled trials assessing efficacy andtolerability of SNRI treatment are presented anddiscussed along with consideration of the potentialadvantages for SNRIs over SSRIs in the treatment ofanxiety disorders.

NEUROBIOLOGICAL BASES OF ANXIETYDISORDERS

Neurochemical aspects of anxiety disorders

Investigations have evaluated the role of disturbancesof different neurotransmitter systems in the pathogen-

Copyright # 2009 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2010; 25: 17–29.DOI: 10.1002/hup

18 b. dell’osso ET AL.

esis of ADs, in particular in the limbic system,including the amygdala and other structures (Davis,1997; Garakani et al., 2006; LeDoux, 1998). Researchhas focused principally on the role of GABAA/BZDcomplex, the norepinephrine and serotonin systems(Gorman et al., 2002).GABAA receptors are thought to modulate

anxiety responses through projections to limbic areaswith a resultant decrease in turnover of monoamines,and to the locus coeruleus and raphe nuclei withsuppression of neuronal firing (Kardos, 1999). Inparticular, it has been hypothesized that down-regulation of the GABAA-benzodiazepine receptor inanxiety disorders would result in a decreased functionof endogeneous neurotransmitters and the expressionof characteristic symptoms (Argyropoulos and Nutt,2003).The norepinephric neurons of the locus coeruleus

give rise to diffuse projections to the forebrain, andmay play a critical role in mediating response to fear,stress and arousal (Bremner et al., 1996). The centraleffects of norephinephrine are mediated throughpostsynaptic a1 and b1 receptors and presynaptic a2receptors which are important in mediating thepresynaptic inhibition of norephinephrine release(‘autoreceptors’) and the release of other neurotrans-mitters, when located on the terminals of non-noradrenergic neurons. The a2-adrenergic receptor

antagonist yohimbine increases the firing of noradren-ergic cell bodies in the locus coeruleus andinduces anxiety, whereas agents that reduce the firingof these neurons, such as the a2 receptor agonistclonidine reduce symptoms of anxiety (Grimsley,1995).Serotonergic neurons located in the raphe nuclei

project to large areas of the brain, including the limbicsystem and hypothalamus and are integrally involvedin the mediation of anxiety responses (Ressler andNemeroff, 2000). Presynaptic 5-HT1 receptors andpostsynaptic 5-HT2 receptors are principally involvedin the modulation of anxiety (Salzman et al., 1993).Stimulation of terminal 5-HT1 autoreceptors attenuatesthe release of serotonin at the nerve ending (Stahl,1998). Studies of the plasma concentrations ofserotonin and its metabolites and receptors havesuggested a dysfunction of the serotonergic system;for example, levels of 5-HT in the cerebrospinal fluidwere reported to be low in patients with anxietydisorders (Johnson and Lydiard, 1995) and adminis-tration of m-chlorophenylpiperazine, a non-selective5HT1 and 5HT2 agonist, leads to an increase ofhostility and anxiety in patients with GAD (Germineet al., 1992). It has been hypothesized that SSRIs mayact through reducing central 5-HT transmission,suggesting there may be a state of increasedserotonergic function in anxiety disorders. However,twomajor serotonergic systems—one originating fromthe medial raphe nuclei, the other from the dorsal raphenuclei—have been implicated in anxiety, it beinghypothesized that each system mediates differentaspects of anxiety, and that dysfunction of one orboth of these systems would result in differing forms ofanxiety disorders (Deakin and Graeff, 1991; Bell andNutt, 1998).While gabaergic, noradrenergic and serotonergic

systems still represent the main focus of attention inrelation to the pathophysiology of ADs and to themechanism of action of different anxiolytic treatments,researchers are moving their efforts to assess theimportance of the balance between these systems andof other transmitters and modulators.

Structural bases of anxiety and neuroimaging datain ADs

Functional imaging techniques have been usedintensively to identify possible neurobiological corre-lates between core anxiety symptoms and anatomicaland neurophysiological alterations in the centralnervous system (Kilts, 2003). Robust evidenceindicates that the amygdala mediates states of

Table 1. FDA approved drugs for the treatment of anxiety disorders

Panic disorder

Benzodiazepines SSRIs SNRIs

Alprazolam Fluoxetine VenlafaxineParoxetineSertraline

Generalized Anxiety Disorder

SSRIs SNRIs Anticonvulsants

Paroxetine Duloxetine PregabalinSertraline VenlafaxineEscitalopramSocial Anxiety Disorder

SSRIsParoxetineSertralinePost-Traumatic Stress Disorder

SSRIsParoxetineSertralineObsessive-Compulsive Disorder

Tryciclics SSRIsClomipramine Fluoxetine

FluvoxamineSertraline


snris in anxiety disorders 19

increased arousal and fear responses (Ohman, 2005).The central nucleus of the amygdala receivesinformation from the visual, auditory, olfactory,nocioceptive and visceral pathways, and mediatesthe integration of information and execution ofautonomic and behavioural fear responses (Kalinet al., 2004). Two types of fear responses have beendescribed: a rapid, less finely tuned mode, in responseto immediate threats and activated by a direct pathwayfrom the sensory thalamus to the amygdala, and aslower one that is activated by a thalamo-cortico-amygdalo circuit and which allows valuable corticalassessments 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 thepathophysiology of anxiety disorders (Shin et al.,2006). The hippocampus is considered to have a role inthe processing of contextual information, differentiat-ing between safe versus potentially dangerous con-texts; hippocampal dysfunction, consequently, mayproduce an anxiety response to innocuous stimuli withan overestimation of potentially threatening contexts(Shin et al., 2006). The medial prefrontal cortex mayplay a critical role in the process of extinction, definedas the reduction of conditioned fear responses when atone is repeatedly presented without a shock previouslyassociated with the tone (Milad and Quirk, 2002). Inanimal models, individuals with dysfunctions in themedial prefrontal cortex seem to have difficulties inmemorizing previous associations between potentiallythreatening stimuli and lack of shock (Tamminga,2006).Structural and functional imaging studies have

highlighted the role of different brain areas such asthe temporal lobe, prefrontal cortex, insula and motorstriatal regions in the neural circuitry of PD (Graeff andDel-Ben, 2008). The most consistent findings suggest:(1) the presence of a left-to-right asymmetry inhippocampal metabolism; (2) hypometabolism inparieto-tempopral areas which may rectify on treat-ment and (3) changes in anterior cingulate or orbito-frontal metabolism (Malizia, 2003).Studies in patients with PTSD suggest a hyper-

responsivity of the amygdala and deficient activation ofthe ventral/medial prefrontal cortex and hippocampus(Liberzon and Sripada, 2008). Structural imagingstudies have reported smaller volumes of ventral/medial prefrontal cortex and hippocampus in patientswith PTSD, when compared to healthy controls (Karlet al., 2006).In SAD, functional neuroimaging studies have

shown that patients differ from normal controls in

the processing of social threat-related stimuli andconditioned aversive stimuli (Malizia, 2003); inparticular, fMRI studies have shown the involvementof both the amygdala and hippocampus (Etkin andWager, 2007).In OCD, obsessions have been associated with over-

activity of the frontal cortex, possibly as a consequenceof impaired thalamic ‘gating’, attributable in turn todeficient striatal function; by contrast, compulsionsmay be the result of aberrant striatal activity (Saxenaand Rauch, 2000). Resting state PET and SPECTstudies in patients with OCD showed increased activityin the orbifrontal cortex and striatum, when comparedto healthy controls (Whiteside et al., 2004). An fMRIstudy has found a significant correlation betweenanxiety 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 basalganglia in GAD, when compared to healthy controls,after benzodiazepine treatment (Wu et al., 1991). Morerecently, an fMRI study found that individualdifferences in the degree of rostral anterior cingulatecortex and amygdala activation predicted bettertreatment outcomes to venlafaxine (Whalen et al.,2008).Taken together, these neuroimaging findings have

led some to hypothesize a potential neurobiologicalclassification of the anxiety disorders, based onpredominant involvement of the amygdala (SAD),the combination of amygdala and cortical involvement(PTSD and PD), or on predominant involvement ofcortico-striatal systems; however, there is at presentinsufficient consistent evidence to categorize GAD andOCD according to this scheme (Cannistraro andRauch, 2003). Nevertheless, scientific advancesin neurobiology are progressively elucidating funda-mental brain mechanisms and the areas underlyinganxiety, and this should eventually provide a rationalbase for pharmacological treatment in anxiety dis-orders.Detailed description of the genetic bases of anxiety

disorders is beyond the scope of this review, but arobust body of evidence from family, twin and adopteestudies indicates a complex genetic component isinvolved in the development of anxiety-related traits(Hettema et al., 2001). For example, allelic variation of5-HT transporter expression and function, in particular,seems to play a crucial role in the vulnerability toanxiety disorders. In addition, a specific association ofthe 5-HT transporter polymorphism and amygdalaactivation is supported by the findings of a recent meta-analysis (Munafo et al., 2008).



MECHANISM OF ACTION OF SNRIs

SNRIs bind to 5-HTand norepinephrine transporters toselectively inhibit the reuptake of these neurotrans-mitters from the synaptic clefts, and therefore have adual mode of action to increase the availability of 5-HTand norepinephrine within the central nervous system.The rationale for use of SNRIs comes from thepossibility to correct dysfunctions of central seroto-nergic and noradrenergic functions which are thoughtto play a critical role in the pathophysiology of anxietydisorders. In addition, SNRIs have the advantage to actsimultaneously on different areas of functioning thatsome authors ascribe to particular monoamines (forexample, aggression to 5-HT, and deficits in motivationto norepinephrine) (Healy and McMonagle, 1997;Stahl, 1999). The class of SNRIs currently includes thefollowing agents: venlafaxine and its active metabolitedrug desvenlafaxine, duloxetine and milnacipran(Table 2).

Venlafaxine

Venlafaxine was the first SNRI to be introduced. It isa bicyclic phenylethylamine compound (Thase andSloan, 2006). After oral administration Venlafaxine iswell absorbed from the gastrointestinal tract andundergoes extensive hepatic first-pass metabolism.Peak plasma concentrations are achieved within 2 h oforal intake and steady-state plasma concentrations are

reached within 4 days of treatment. Renal eliminationis the primary route of excretion. Both venlafaxine andits active metabolite, O-desmethylvenlafaxine(ODV) have linear kinetics. Venlafaxine is availablein both immediate-release (IR) and extended release(XR) formulations: the extended release formulationsimplifies administration, as once-daily dosingachieves similar bioavailability to that with thetwice-daily dose. The starting dose is generally75mg/day and the recommended maximum dose is375mg/day. Reduced doses are recommended inpatients with hepatic cirrhosis and severe renal disease.In healthy elderly patients, however, dose adjustmentsmay not be necessary (Kent, 2000). Both venlafaxineand its metabolites have little affinity for muscarinic,cholinergic, H1-histaminic or a-adrenergic receptors,and have no monoamine oxidase A or B inhibitoryactivity (Kent, 2000). Venlafaxine is though to actprimarily as an SSRI at low therapeutic dosages(<100mg/day), only becoming a dual reuptakeinhibitor as the dosage increases (Kelsey, 1996;Roseboom and Kalin, 2000).

Desvenlafaxine

Desvenlafaxine is the only major active metaboliteof venlafaxine and like the parent compound is wellabsorbed after oral administration (80% bioavailabil-ity) with a half-life of approximately 9–10 h. The time

Table 2. Pharmacokinetics of SNRIs

Venlafaxine IR/SR Desvenlafaxine (ODV) Duloxetine Milnacipran

Therapeutic dose range(mg/day)

75–225 (divided dose IR)(single dose SR)

50 60–120 (with a maximumof 60mg each dose)

25–200

Bioavailability 45% 80.5% 50% (reduced of a third in smokers) 85%Biotransformation pathways CYP2D6 and others CYP3A4 (minimal) CYP2D6 and CYP1A2. CYP2D6 or CYP2C19Major metabolites O-desmethyl-venlafaxine

(ODV) (active)No active metabolites 4-hydroxy duloxetine

glucuronide and 5-hydroxy,6-methoxy duloxetinesulfate (no active)

No active metabolites

Half-life 4 h (parent) 10 h 12 h (parent) 12 h (parent)Elimination routes Urine (87%) Urine unchanged, heces

metabolitesUrine unchanged (<1%),

urine metabolites (about 70%),heces metabolites (about 20%)

Urine unchanged(50%), urine conjugated (30%),

urine oxidized (20%)Protein binding 27% (parent) 30% >90% (parent) 13% (parent)NE/5-HT affinity ratio 15.7 13.8 9.3 2



to maximum concentration is 7.5 h, and steady-stateconcentrations of desvenlafaxine are reached within 3–4 days of treatment. The compound has low proteinbinding, independent of its concentration. The recom-mended dose of desvenlafaxine is 50mg/day, withoutregard to meals. Elimination occurs in the form of aglucuronide conjugate metabolite, with a low possib-ility of drug interactions (Septien-Velez et al., 2007). Inaddition, the inhibition of CYP450 enzymes by theagent is minimal (Shilling et al., 2005). Desvenlafaxinehas a NE/5-HT affinity ratio of 13.8 (Roseboom andKalin, 2000), and when compared to VEN itsnorepinephrine-binding affinity is almost three timeshigher (Sopko et al., 2008). The main pharmacokineticdifference between desvenlafaxine and its parent drugis the route of metabolism: whereas venlafaxine ismetabolized primarily by CYP2D6, desvenlafaxine isconjugated via uridine diphosphate glucuronyl trans-ferase (UGT), and therefore there may be morepotential drug interactions for venlafaxine thandesvenlafaxine during concomitant administrationwith other medications that affect the CYP2D6pathway (Sopko et al., 2008).

3.3 Duloxetine

Duloxetine shows linear kinetics at the therapeuticdosage (60–120mg/day). The mean elimination half-life is 12.5 h and steady concentration is reached within3 days at each dose (Hunziker et al., 2005). Duloxetineundergoes phase I oxidation carried out by cytochromeP450 isozymes CYP2D6 and CYP1A2; oxidizedduloxetine is then conjugated with glucuronic acid.The primary metabolite observed in plasma is theglucuronide conjugate of 4-hydroxy duloxetine.Intermediate unconjugated metabolites are not detect-able in significant levels in plasma so that conjugationof oxidized duloxetine must occur rapidly. Theconjugated metabolites have low affinity for the 5-HT, NE or dopamine transporter and are considered tobe inactive (Kuo et al., 2004). Elimination is primarilyrenal, with 72% excreted in the urine and 19% infaeces, the latter resulting from biliary excretion (Lantzet al., 2003). Duloxetine inhibits the uptake of 5HTand

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

Milnacipran

Milnacipran shows linear pharmacokinetics over adose range of 25–200mg/day. It is rapidly andextensively absorbed (>85%) and has a half-life of12 h with steady-state reached within 48 h whenadministrated twice a day (Delini-Stula, 2000).Milnacipran is not metabolized by cytocrome P450and is eliminated by renal excretion (Preskorn, 2004);as a consequence, clearance is significantly prolongedin patients with renal failure, with a half-life threetimes longer than in normal volunteers (Puozzo et al.,1998b). By contrast its pharmacokinetic properties areessentially unchanged in patients with severe liverimpairment (Puozzo et al., 1998a). Plasma proteinbinding is low and non-saturable. None of itsmetabolites have meaningful pharmacological activityat clinical levels. The NE/5-HT affinity ratio ofmilnacipran is 2:1 (Puozzo et al., 2002), this beingthe closest to a 1:1 ratio of all the SNRIs.

RANDOMIZED CONTROLLED TRIALS ANDOPEN STUDIES WITH SNRIs IN ANXIETYDISORDERS

Panic disorder

Two early open-label case series provided preliminaryindications of the efficacy of venlafaxine in thetreatment of PD even at low dosages (37.5 to 75mg/day) (Geracioti, 1995; Papp et al., 1998). A subsequentdouble-blind placebo-controlled study of 8 weeks in asample of 25 patients found more certain evidence ofefficacy (Pollack et al., 1996). Although one placebo-controlled investigation found rather mixed evidenceof efficacy (Bradwejn et al. 2005), a later study foundthat venlafaxine (225mg/day) had statistically superiorresponse and remission rates versus placebo, goodoverall tolerability and similar efficacy to the SSRIparoxetine (40mg/day) in short-term treatment in a12-week study involving 664 patients (Pollack et al.,2007). Venlafaxine also has long-term efficacy and a26-week double-blind placebo-controlled relapse pre-



vention study in patients who had previouslyresponded to open treatment found significantly fewerrelapses during continuation treatment with venlafax-ine (Ferguson et al., 2007).There is only limited data for the efficacy of other

SNRIs in PD. A single case report describes successfultreatment with duloxetine 60mg/day (Crippa andZuardi, 2006), and a 10-week open-label study in 31patients found milnacipran to be effective at doses of50–100mg/day, 58% of the sample achieving sympto-matic remission (Blaya et al., 2007).

Generalized Anxiety Disorder (GAD)

Many placebo-controlled studies have demonstratedthat venlafaxine-XR is effective in reducing both thesomatic and psychological symptoms of GAD at dosesof 75–225mg/day (Davidson et al., 1999; Hackett,2000; Rickels et al., 2000) and in preventing relapsesduring 6-month double-blind treatment (Allgulanderet al., 2001; Gelenberg et al., 2000). Comparisons ofthe SSRIs paroxetine and escitalopram with venlafax-ine did not find any difference of efficacy in acutetreatment of GAD although these trials may have hadinsufficient power to distinguish reliably betweentreatments (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 findconsistent evidence of efficacy for duloxetine in acutetreatment (Allgulander et al., 2007; Endicott et al.,2007; Hartford et al., 2007; Koponen et al., 2007; Rynnet al., 2008). With the exception of the multicentretrial of Koponen et al. (2007) in which a fixed dosewas administered, all studies lasted 9–10 weeks andemployed flexible doses (60–120mg/die) (Allgulanderet al., 2007; Endicott et al., 2007; Rynn et al., 2008).Long-term efficacy was demonstrated through thefindings of a double-blind placebo-controlled relapseprevention study (Davidson et al., 2008). Duloxetine isefficacious in reducing significant pain symptoms(Russell et al., 2007), and has similar efficacy tovenlafaxine in reducing somatic symptoms (Nicoliniet al., 2008).For milnacipran, data is only limited. A pre-clinical

study suggested that chronic administration of milna-cipran at doses of 50–100mg/day/kg had the potentialto be beneficial in reducing anxiety symptoms (Moojenet al., 2006); and a case series of schizophrenic patientswith intense anxiety symptoms, treated with clozapineand milnacipran at a dose of 100mg/day suggested a

significant improvement in anxiety (Gama et al.,2006).

Social Anxiety Disorder (SAD)

An early 15-week open-label study suggested theefficacy of flexible doses of venlafaxine (112.5–187.5mg/day) in patients who had not responded toSSRI treatment (Altamura et al., 1999).A subsequent multicentre randomized, double-blind,

placebo-controlled, parallel group study found thatvenlafaxine-XR (75–225mg/day) had significantsuperiority over placebo in the short-term treatment,with efficacy and tolerability similar to that ofparoxetine (20–50mg/day) (Liebowitz et al., 2005a).Further double-blind placebo controlled trials haveconfirmed the efficacy of venlafaxine-XR (75–225mg/day) in both short- and long-term treatment (Allgu-lander 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 describedthe successful acute treatment of two patients withduloxetine at the dosage of 120mg/day (Crippa et al.,2007), and 12 weeks of treatment with milnacipran wasbeneficial in six out of 11 patients with Taijin-Kyofusho (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 anddepressive symptoms, treated with venlafaxine for6 weeks reported a significant reduction in symptomseverity and improvement in global functioning(Smajkic et al., 2001). More recently, a 6-monthdouble-blind placebo-controlled study showed thatflexible doses of venlafaxine-XR (37.5–300mg/day)were effective and generally well-tolerated (Davidsonet al., 2006a). A parallel 12-week, multicentre, double-blind, placebo-controlled study suggested that venla-faxine (37.5–300mg/day) was superior to placebo inimproving PTSD symptoms, whereas sertraline (25–200mg/day) was not (Davidson et al., 2006b).Only limited data are available regarding the use of

duloxetine in patients with PTSD. Combination ofelectroconvulsive therapy with both duloxetine andolanzapine produced full remission in a patient withPTSD and comorbid major depressive disorder(Hanretta and Malek-Ahmadi, 2006). There are asyet no published studies with milnacipran in patientswith PTSD.



Obsessive-Compulsive Disorder (OCD)

Double-blind comparative studies support the efficacyof venlafaxine in patients with OCD and a previouspoor response to SSRI treatment (Dell’Osso et al.,2006). An open naturalistic study of 39 patients withOCD (29 being regarded as treatment-resistant) foundthat venlafaxine was effective (Hollander et al., 2003).A 12-week randomized double-blind comparativestudy found that venlafaxine was equally effective toparoxetine in treating OCD (Denys et al., 2003). Aprevious study, however, did not support the efficacy ofvenlafaxine in OCD (Yariyura-Tobias and Neziroglu,1996).No randomized placebo-controlled studies of dulox-

etine in patients with OCD have yet been published,although it may be helpful in treatment-resistantpatients, as suggested in a recent case-series of OCDpatients with comorbid mood/anxiety disorders whohad not responded to previous treatment with serotoninreuptake inhibitors (SRIs) at adequate doses for at least12 weeks, (Dell’Osso et al., 2008). A pre-clinical studywith milnacipran, administered at dosages >10mg/day, showed inhibition of marble burying behaviour inmice (an animal model of OCD), suggesting potentialefficacy 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 efficacy of thismolecule in reducing anxiety symptoms in patientswith major depressive disorder (Tourian et al., 2007).

SAFETY AND TOLERABILITY DATA

Most patients with anxiety disorders will require long-term treatment, particularly those with the most severesymptoms (Kjernisted and Bleau, 2004). Howevermany will stop treatment prematurely due to the onsetof side effects (Devane et al., 2005). SSRI treatmentgenerally shows lower rates of treatment discontinu-ation than with tricyclic antidepressants (McManuset al., 2004), but many patients experience troublesomeside effects; indeed, a recent primary care study foundthat SSRIs were the most frequent class of drugresponsible for adverse effects (Gandhi et al., 2003).Two common stated reasons for discontinuation ofSSRIs treatment are sexual dysfunction and weightgain; a naturalistic long-term comparison of SSRIs inthe treatment of PD found rates of 6.3–8.2% for weightgain and 5–15% for sexual dysfunction (Dannon et al.,2007).Venlafaxine may have some advantage over SSRIs in

terms of reduced propensity for weight gain (Kim

et al., 2006), although not for sexual dysfunction(Gregorian et al., 2002). By contrast, elevation of bloodpressure is more common in patients treated withvenlafaxine when compared to those undergoing SSRItreatment; although a recent naturalistic study in 37patients treated with high venlafaxine doses (225–525mg) found a favourable cardiovascular profile(Mbaya et al., 2007).A review of the prevalence of sexual dysfunction

with antidepressants suggested that duloxetine was theleast likely to provide these side effects (Wernekeet al., 2006). Meta-analysis of four double-blindstudies found that patients receiving duloxetine (40–120mg/day) had lower rates of sexual dysfunctionduring the first 8 weeks of treatment, when compared topatients receiving paroxetine (20mg/day) (Delgadoet al., 2005). A recent placebo controlled study ofduloxetine versus escitalopram in depressed patientsfound an incidence of treatment-emergent sexualdysfunction of 33.3% for duloxetine, 43.6% forescitalopram and 25.0% for placebo (Clayton et al.,2007). Duloxetine appears to have time-coursedependent effect on body weight, with slight weightloss during short-term treatment and subsequentmodest weight gain over the long-term (Wise et al.,2006).Data for the other SNRIs is limited. A recent meta-

analysis of 16 randomized controlled trials conductedin depressed patients reported that milnacipran showedsimilar tolerability to other antidepressants in the short-term, but fewer adverse events and lower prematurewithdrawal rates (Nakagawa et al., 2008). Milnacipranis associated with the development of sexual dysfunc-tion, although in the majority of patients sexualfunction improves as depressive symptoms reduce(Baldwin et al., 2008). Considerations of desvenlafax-ine are based on its safety profile in depressed patients;in general, the tolerability profile is nearly identical tothat of venlafaxine, the most common side-effectsbeing nausea, insomnia, somnolence and dizziness(Sopko et al., 2008).

DISCUSSION

Anxiety disorders are common conditions associatedwith a considerable functional impairment (Carpinielloet al., 2002; Demertzis and Craske, 2006). Early diag-nosis and long-term treatment are important for improv-ing quality of life of patients as longer duration ofuntreated illnessmay be associatedwith a less favourablecourse of illness (Altamura et al., 2005, 2008).SSRIs and cognitive-behaviour therapy are held to

be the principal treatments for patients with anxiety



disorders, but cannot be regarded as ‘ideal’. A potentialadvantage for SNRIs is the selective double action onboth norepinephrine and serotonin, as this has beenfound to offer some advantage over conventional SSRItreatment in depressed patients (Silverstone, 2004).Meta-analyses have indicated that treatment of majordepressive disorder with venlafaxine achieves greaterresponse and remission rates than is seen withconventional 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 statewhether thismight also translate into superiority for SNRIs whencompared to SSRIs in anxiety disorders (Machadoet al., 2006). The relative onset of action of SNRIs andSSRIs in anxiety disorders deserves further research, asat least one placebo-controlled study with venlafaxinein GAD and a placebo-controlled study with duloxetinein depressed patients showed a significant reduction inanxiety 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 moodand substance use disorders (Belzer and Schneier,2004; Brady et al., 2007). Venlafaxine has been foundeffective in patients with anxiety disorders complicatedby other psychiatric conditions (Feighner et al., 1998;Khan et al., 1998; Rudolph et al., 1998), and duloxetinehas been found beneficial in patients with physical ill-health arising from diabetic neuropathic pain andfibromyalgia (Sultan et al., 2008). Furthermore, SNRIshave been usefully combined with atypical antipsy-chotics in patients with co-morbid mood and anxietydisorders (McIntyre et al., 2007).Another potential advantage for SNRIs over other

compounds in the treatment of anxiety disorders mayreside in the specific efficacy of these compounds inrelieving somatic symptoms which represent a coredimension of many disorders. This effect has beenalready reported in patients with major depressivedisorder and somatic complaints and in patients withanxiety disorders but needs further investigation(Barkin and Barkin, 2005).

CONCLUSIONS

Over the last two decades, there has been muchprogress in our understanding of the epidemiology,neurobiology and treatment of anxiety disorders.Whilst SSRIs are regarded as first-line pharmacologi-cal treatments in most anxiety disorders, SNRIs arereceiving increasing consideration, and venlafaxineand duloxetine have already received regulatory

approvals for some disorders. In depression, SNRItreatment may combine a shorter latency of onset withhigher rates of overall remission than is seen withconventional SSRIs, and may be of particular value inpatients with comorbid physical symptoms. Thesepotential advantages cannot yet be regarded asconfirmed but even modest differences in efficacyand tolerability for one treatment approach overanother may have important public health implicationsgiven the high prevalence, disability and chronic natureof these conditions.

REFERENCES

Allgulander C, Bandelow B, Hollander E, et al. 2003. WCA recommen-dations for the long-term treatment of generalized anxiety disorder. CNSSpectr 8: 53–61.

Allgulander C, Hackett D, Salinas E. 2001. Venalfaxine extended release(ER) in the treatment of generalized anxiety disorder: twenty-four-weekplacebo controlled dose-ranging study. Br J Psychiatry 179: 15–22.

Allgulander C, Hartford J, Russell J, et al. 2007. Pharmacotherapy ofgeneralized anxiety disorder: results of duloxetine treatment from apooled analysis of three clinical trials. Curr Med Res Opin 23: 1245–1252.

Allgulander C,Mangano R, Zhang J, et al. 2004. Efficacy of Venlafaxine ERin patients with social anxiety disorder: a double-blind, placebo-con-trolled, parallel-group comparison with paroxetine. Hum Psychophar-macol 19: 387–396.

Alonso J, Angermeyer MC, Bernert S, et al. European Study of theEpidemiology of Mental Disorders (ESEMeD). Project. Prevalence ofmental disorders in Europe: results from the European Study of theEpidemiology of Mental Disorders (ESEMeD) project. 2004. ActaPsychiatr Scand Suppl 420: 21–27.

Alonso J, Lepine JP. ESEMeD/MHEDEA 2000 Scientific Committee. 2007.Overview of key data from the European Study of the Epidemiology ofMental Disorders (ESEMeD). J Clin Psychiatry 68: 3–9.

Altamura AC, Pioli R, Vitto M, Mannu P. 1999. Venlafaxine in socialphobia: a study in selective serotonin reuptake inhibitor non-responders.Int Clin Psychopharmacol 14: 239–245.

Altamura AC, Dell’osso B, D’Urso N, Russo M, Fumagalli S, Mundo E.2008. Duration of untreated illness as a predictor of treatment responseand clinical course in generalized anxiety disorder. CNS Spectr 13: 415–422.

Altamura AC, Santini A, Salvadori D, Mundo E. 2005. Duration ofuntreated illness in panic disorder: a poor outcome risk factor? Neurop-sychiatr Dis Treat 1: 345–347.

American Psychiatric Association. 2000.Diagnostic and Statistical Manualof Mental Disorders, 4th edn, Text Revision. American PsychiatryPublishing: Washington DC.

Angst J, Gamma A, Baldwin DS, Ajdacic-Gross V, Rossler W. 2009. Thegeneralized anxiety spectrum: prevalence, onset, course and outcome.Eur Arch Psychiatry Clin Neurosci 259: 37–45.

Argyropoulos SV, Nutt DJ. 1999. The use of benzodiazepines in anxiety andother disorders. Eur Neuropsychopharmacol 9: 407–412.

Argyropoulos SV, Nutt DJ. Neurochemical aspects of anxiety. In AnxietyDisorders, Chap 11, Nutt DJ, Ballenger JC (eds). 2003. BlackwellScience Ltd: Malden, MA; 181–199.

Baldwin DS. 2004. Sexual dysfunction associated with antidepressantdrugs. Expert Opin Drug Saf 3: 457–470.

Baldwin DS. 2006. Evidence-based guidelines for anxiety disorders: canthey improve clinical outcomes? CNS Spectr 11: 34–39.

Baldwin DS, Ajel K. 2007. The role of pregabalin in the treatment ofgeneralized anxiety disorder.Neuropsychiatric Disease Treat 3: 185–191.

Baldwin DS, Anderson IM, Nutt DJ, et al. 2005. Evidence-based guidelinesfor the pharmacological treatment of anxiety disorders: recommendationsfrom the British Association for Psychopharmacology. J Psychophar-macol 19: 567–596.



Baldwin DS, Moreno R, Briley M. 2008. Resolution of sexual dysfunctionduring acute treatment of major depression with milnacipran. HumPsychopharmacol 23: 527–532.

Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ. World Federationof Societies of Biological Psychiatry Task Force on Treatment Guidelinesfor Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders.2002. World Federation of Societies of Biological Psychiatry (WFSBP)guidelines for the pharmacological treatment of anxiety, obsessive-com-pulsive and posttraumatic stress disorders. World J Biol Psychiatry 3:171–199.

Barkin RL, Barkin S. 2005. The role of venlafaxine and duloxetine in thetreatment of depression with decremental changes in somatic symptomsof pain, chronic pain, and the pharmacokinetics and clinical consider-ations of duloxetine pharmacotherapy. Am J Ther 12: 431–438.

Bell CJ, Nutt DJ. 1998. Serotonin and panic. Br J Psychiatry 172: 465–471.Belzer K, Schneier FR. 2004. Comorbidity of anxiety and depressivedisorders: issues in conceptualization, assessment, and treatment.J Psychiatr Pract 10: 296–306.

Blaya C, Seganfredo AC, Dornelles M, et al. 2007. The efficacy ofmilnacipran in panic disorder: an open trial. Int Clin Psychopharmacol22: 153–158.

Bose A, Korotzer A, Gommoll C, Li D. 2008. Randomized placebo-controlled trial of escitalopram and venlafaxine XR in the treatmentof generalized anxiety disorder. Depress Anxiety 25: 854–861.

Bradwejn J, Ahokas A, Stein DJ, Salinas E, Emilien G, Whitaker T. 2005.Venlafaxine extended-release capsules in panic disorder: flexible-dose,double-blind, placebo-controlled study. Br J Psychiatry 187: 352–359.

Brady KT, Verduin ML, Tolliver BK. 2007. Treatment of patients comorbidfor addiction and other psychiatric disorders. Curr Psychiatry Rep 9:374–380.

Bremner JD, Kristal JH, Southwick SM, Charney DS. 1996. Noradrenergicmechanisms in stress and anxiety: I. Preclinical studies. Synapse 23: 28–38.

Cannistraro PA, Rauch SL. 2003. Neural circuitry of anxiety: evidence fromstructural and functional neuroimaging studies. Psychopharmacol Bull37: 8–25.

Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. 2007.Changes in sexual functioning associated with duloxetine, escitalopram,and placebo in the treatment of patients with major depressive disorder.J Sex Med 4: 917–929.

Carpiniello B, Baita A, Carta MG, et al. 2002. Clinical and psychosocialoutcome of patients affected by panic disorder with or without agor-aphobia: results from a naturalistic follow-up study. Eur Psychiatry 17:394–398.

Crippa JA, Zuardi AW. 2006. Duloxetine in the treatment of panic disorder.Int J Neuropsychopharmacol 9: 633–634.

Crippa JA, Filho AS, Freitas MC, Zuardi AW. 2007. Duloxetine in thetreatment of social anxiety disorder. J Clin Psychopharmacol 27: 310.

Dannon PN, Iancu I, Lowengrub K, et al. 2007. A naturalistic long-termcomparison study of selective serotonin reuptake inhibitors in the treat-ment of panic disorder. Clin Neuropharmacol 30: 326–334.

Davidson JR. 2003. Pharmacotherapy of social phobia. Acta PsychiatrScand Suppl 417: 65–71.

Davidson JR, DuPont RL, Hedges D, Haskins JT. 1999. Efficacy, safety andtolerability of venlafaxine extended release and buspirone in outpatientswith generalized anxiety disorder. J Clin Psychiatry 60: 528–535.

Davidson J, Baldwin D, Stein DJ, et al. 2006a. Treatment of posttraumaticstress disorder with venlafaxine extended release: a 6-month randomizedcontrolled trial. Arch Gen Psychiatry 63: 1158–1165.

Davidson J, Rothbaum BO, Tucker P, Asnis G, Benattia I, Musgnung JJ.2006b. Venlafaxine extended release in posttraumatic stress disorder: asertraline- and placebo-controlled study. J Clin Psychopharmacol 26:259–267.

Davidson JR, Wittchen HU, Llorca PM, et al. 2008. Duloxetine treatmentfor relapse prevention in adults with generalized anxiety disorder: adouble-blind placebo-controlled trial. Eur Neuropsychopharmacol 18:673–681.

Davis M. 1997. Neurobiology of fear responses: the role of amygdale.J Neuropsychiatry Clin Neurosci 9: 382–402.

De Girolamo G, Polidori G, Morosini P, et al. 2006. Prevalence of commonmental disorders in Italy: results from the European Study of theEpidemiology of Mental Disorders (ESEMeD). Soc Psychiatry PsychiatrEpidemiol 41: 853–861.

Deakin JFW, Graeff FG. 1991. 5-HT and mechanisms of defense.J Psychopharmacol 5: 305–315.

Delgado PL, Brannan SK, Mallinckrodt CH, et al. 2005. Sexual functioningassessed in 4 double-blind placebo- and paroxetine-controlled trials ofduloxetine for major depressive disorder. J Clin Psychiatry 66: 686–692.

Delini-Stula A. 2000. Milnacipran: an antidepressant with dual selectivityof action on noradrenaline and serotonin uptake. Hum Psychopharmacol15: 255–260.

Dell’Osso B, Mundo E, Marazziti D, Altamura AC. 2008. Switching fromserotonin reuptake inhibitors to duloxetine in patients with resistant obsessivecompulsive disorder: a case series. J Psychopharmacol 22: 210–213.

Dell’Osso B, Nestadt G, Allen A, Hollander E. 2006. Serotonin-norepi-nephrine inhibitors in the treatment of obsessive-compulsive disorder: acritical review. J Clin Psychiatry 67: 600–610.

Demertzis KH, Craske MG. 2006. Anxiety in primary care. Curr PsychiatryRep 8: 291–297.

Denys D, van der Wee N, van Megen HJ, Westenberg HG. 2003. A doubleblind comparison of venlafaxine and paroxetine in obsessive-compulsivedisorder. J Clin Psychopharmacol 23: 568–575.

Detke MJ, Lu Y, Goldstain DJ, McNamara RK, Demitrack MA. 2002.Duloxetine 60mg once daily dosing versus placebo in the acute treatmentof major depression. J Psych Res 36: 383–390.

Devane CL, Chiao E, Franklin M, Kruep EJ. 2005. Anxiety disorders in the21st century: status, challenges, opportunities, and comorbidity withdepression. Am J Manag Care 11: 344–353.

Endicott J, Russell JM, Raskin J, et al. 2007. Duloxetine treatment for rolefunctioning improvement in generalized anxiety disorder: three indepen-dent study. J Clin Psychiatry 68: 518–524.

Etkin A, Wager TD. 2007. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, andspecific phobia. Am J Psychiatry 164: 1476–1488.

Feighner JP, Entusuah AR, McPherson MK. 1998. Efficacy of once-dailyvenlafaxine extended release (XR) for symptoms of anxiety in depressedoutpatients. JAD 47: 55–62.

Ferguson JM, Khan A, Mangano R, Entsuah R, Tzanis E. 2007. Relapseprevention of panic disorder in adult outpatient responders to treatmentwith venlafaxine extended release. J Clin Psychiatry 68: 58–68.

Fontenelle LF, Mendlowicz MV, Versiani M. 2006. The descriptive epide-miology of obsessive-compulsive disorder. Prog NeuropsychopharmacolBiol Psychiatry 30: 327–337.

Gama CS, Zanatto VC, Picon F, Lobato MI, Belmonte-de-Abreu PS. 2006.Efficacy of milnacipran in treating anxiety symptoms in schizophrenicpatients receiving clozapine: a case series study. Rev Bras Psiquiatr 28:339–340.

Gandhi TK, Weingart SN, Borus J, et al. 2003. Adverse drug events inambulatory care. N Engl J Med 17: 1556–1564.

Garakani A, Mathew SJ, Charney DS. 2006. Neurobiology of anxietydisorders and implications for treatment. Mt Sinai J Med 73: 941–949.

Gelenberg AJ, Lydiard RB, Rudolph RL, Aguiar L, Haskins JT, Salinas E.2000. Efficacy of venlafaxine extended-release capsules in nondepressedoutpatients with generalized anxiety disorders: a 6-month randomizedcontrolled trial. JAMA 283: 3082–3088.

Geracioti TD Jr. 1995. Venlafaxine treatment of panic disorder: a caseseries. J Clin Psychiatry 56: 408–410.

Germine M, Goddard AW, Woods SW, Charney DS, Heninger GR. 1992.Anger and anxiety responses to m-chlorophenylpiperazine in generalizedanxiety disorder. Biol Psychiatry 32: 457–461.

Gorman JM, Hirschfeld RMA, Ninan PT. 2002. New developments in theneurobiological basis of anxiety disorders. Psychopharmacol Bull 36:49–67.

Graeff FG, Del-Ben CM. Neurobiology of panic disorder: from animalmodels to brain neuroimaging. Neurosci Biobehav Rev 2008 32: 1326–1335.

Gregorian RS, Golden KA, Bahce A, Goodman C, Kwong WJ, Khan ZM.2002. Antidepressant-induced sexual dysfunction.Ann Pharmacother 36:1577–1589.



Grimsley SR. 1995. Anxiety disorders. In Applied Therapeutics: TheClinical Use of Drugs, 6th edn, Vol. 76, Young LY, Koda-KimbleMA (eds). Applied Therapeutics Inc: Vancouver, Canada; 1–28.

Hackett D. 2000. Venlafaxine XR in the treatment of anxiety. Acta PsychiatrScand 406: 30–35.

Hanretta AT, Malek-Ahmadi P. 2006. Combined use of ECTwith duloxetineand olanzapine: a case report. J ECT 22: 139–141.

Hartford J, Kornstein S, Liebowitz M, et al. 2007. Duloxetine as an SNRItreatment for generalized anxiety disorder: results from a placebo andactive-controlled trial. Int Clin Psychopharmacol 22: 167–174.

Healy D, McMonagle T. 1997. The enhancement of social functioning as atherapeutic principle in the management of depression.J Psychopharmacol 11: 25–31.

Hettema JM, Neale MC, Kendler KS. 2001. A review and meta-analysis ofthe genetic epidemiology of anxiety disorders. Am J Psychiatry 158 (10):1568–1578.

Hirschfeld RM. 2000. Antidepressants in long-term therapy: a review oftricyclic antidepressants and selective serotonin reuptake inhibitors. ActaPsychiatr Scand Suppl 403: 35–38.

Hollander E, Friedberg J, Wasserman S, Allen A, Birnbaum M, Koran LM.2003. Venlafaxine in treatment-resistant obsessive-compulsive disorder.J Clin Psychiatry 64: 546–550.

Hunziker ME, Suehs BT, Bettinger TL, Crismon ML. 2005. Duloxetinehydrocloride: a new dual-acting medication for the treatment of majordepressive disorder. Clin Therapheutics 27: 1126–1143.

Johnson MR, Lydiard RB. 1995. The neurobiology of anxiety disorders.Psychiatr Clin North Am 18: 681–725.

Kalin NH, Shelton SE, Davidson RJ. 2004. The role of the central nucleus ofthe amygdala in mediating fear and anxiety in the primate. J Neurosci 16:5506–5515.

Kardos J. 1999. Recent advances in GABA research. Neurochem Int 34:353–358.

Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N, Werner A. 2006.A meta-analysis of structural brain abnormalities in PTSD. NeurosciBiobehav Rev 30: 1004–1031.

Keane TM, Marshall AD, Taft CT. 2006. Posttraumatic stress disorder:etiology, epidemiology, and treatment outcome. Annu Rev Clin Psychol2: 161–197.

Kelsey JE. 1996. Dose-response relationship with venlafaxine. J ClinPsychopharmacol 16: 21–26.

Kent JM. 2000. SNaRIs, NaSSAs and NaRIs: new agents for the treatmentof depression. Lancet 355: 911–918.

Kessler RC, McGonagle KA, Zhao S, et al. 1994. Lifetime and 12-monthprevalence of DSM-III-R psychiatric disorders in the United States.Results from the National Comorbid Survey. Arch Gen Psychiatry 51:8–19.

Kessler RC, Nelson CB, McGonagle KA, Liu J, Swartz M, Blazer DG.1996. Comorbidity of DSM-III-R major depressive disorder in thegeneral population: results from the US National Comorbidity Survey.Br J Psychiatry Suppl 30: 17–30.

Khan A, Upton GV, Rudolp RL, Entsuash R, Leventer SM. 1998. The use ofvenlafaxine in the treatment of major depression and major depressionassociated with anxiety: a dose-response study. Venlafaxine InvestigatorStudy Group. J Clin Psychopharmacol 18: 19–25.

Kilts C. 2003. In vivo neuroimaging correlates of the efficacy of paroxetinein the treatment of mood and anxiety disorders.Psychopharmacol Bul 37:19–28.

Kim TS, Pae CU, Yoon SJ, et al. 2006. Comparison of venlafaxine extendedrelease versus paroxetine for treatment of patients with generalizedanxiety disorder. Psychiatry Clin Neurosci 60: 347–351.

Kjernisted KD, Bleau P. 2004. Long-term goals in the management of acuteand chronic anxiety disorders. Can J Psychiatry 49: 51S–63S.

Koponen H, Allgulander C, Erickson J, et al. 2007. Efficacy of duloxetinefort he treatment of generalized anxiety disorder: implications forprimary care physicians. Prim Care Companion J Clin Psychiatry 9:100–107.

Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB. AmericanPsychiatric Association. 2007. Practice guideline for the treatmentof patients with obsessive-compulsive disorder. Am J Psychiatry 164:5–53.

Kroenke K, Spitzer RL, Williams JB, Monahan PO, Lowe B. 2007. Anxietydisorders in primary care: prevalence, impairment, comorbidity, anddetection. Ann Intern Med 146: 317–325.

Kuo F, Gillespie TA, Kulanthaivel P, et al. 2004. Synthesis and biologicalactivation of some known and putative duloxetine metabolites. BioorgMed Chem Lett 14: 3481–3486.

Lantz RJ, Gillespie TA, Rash TJ, et al. 2003. Metabolism, excretion, andpharmacokinetics of duloxetine in healthy human subjects. Drug MetabDispos 31: 1142–1150.

LeDoux J. 1998. Fear and the brain: where have we been, and where are wegoing? Biol Psychiatry 44: 1229–1238.

Leon AC, Portera L, Weissman MM. 1995. The social costs of anxietydisorders. Br J Psychiatry 27: 19–22.

Lepine JP. 2002. The epidemiology of anxiety disorders: prevalence andsocietal costs. J Clin Psychiatry 63: 4–8.

Liberzon I, Sripada CS. 2008. The functional neuroanatomy of PTSD: acritical review. Prog Brain Res 167: 151–169.

Lieb R, Becker E, Altamura C. 2005. The epidemiology of generalizedanxiety disorder in Europe. Eur Neuropsychopharmacol 15 (4): 445–452.

Liebowitz MR, Gelenberg AJ, Munjack D. 2005a. Venlafaxine extendedrelease vs placebo and paroxetine in social anxiety disorder. Arch GenPsychiatry 62: 190–198.

Liebowitz MR, Mangano RM, Bradwejn J, Asnis G. SAD Study Group.2005b. A randomized controlled trial of venlafaxine extended release ingeneralized social anxiety disorder. J Clin Psychiatry 66: 238–247.

Machado M, Iskedjian M, Ruiz I, Einarson TR. 2006. Remission, dropouts,and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials. Curr Med Res Opin 22: 1825–1837.

Malizia AL. 2003. Brain imaging and anxiety disorders. In Anxiety Dis-orders, Chap 12, Nutt DJ, Ballenger JC (eds). Blackwell Science Ltd:Malden, MA; 201–228.

Mataix-Cols D, Cullen S, Lange K, et al. 2003. Neural correlates of anxietyassociated with obsessive-compulsive symptom dimensions in normalvolunteers. Biol Psychiatry 53: 482–493.

Mbaya P, Alam F, Ashim S, Bennett D. 2007. Cardiovascular effects of highdose venlafaxine XL in patients with major depressive disorder. HumPsychopharmacol 22: 129–133.

McIntyre A, Gendron A, McIntyre A. 2007. Quetiapine adjunct to selectiveserotonin reuptake inhibitors or venlafaxine in patients with majordepression, comorbid anxiety, and residual depressive symptoms: arandomized, placebo-controlled pilot study. Depress Anxiety 24: 487–494.

McManus P, Mant A, Mitchell P, Dudley J. 2004. Length of therapy withselective serotonin reuptake inhibitors and tricyclic antidepressants inAustralia. Aust NZJ Psychiatry 38: 450–454.

Milad MR, Quirk GJ. 2002. Neurons in medial prefrontal cortex signalmemory for fear extinction. Nature 420: 70–74.

Moojen VKM,Martins MR, Reinke A, et al. 2006. Effects of milnacipran inanimal models of anxiety and memory. Neurochem Res 31: 571–577.

Mula M, Pini S, Cassano GB. 2007. The role of anticonvulsant drugs inanxiety disorders: a critical review of the evidence. J Clin Psychophar-macol 27 (3): 263–272.

Munafo MR, Brown SM, Hariri AR. 2008. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. BiolPsychiatry 63: 852–857.

Nagata T, Oshima J, Wada A, Yamada H, Kiriike N, Iketani T. 2003. Opentrial of milnacipran for Taijin-Kyofusho in Japanese patients with socialanxiety disorder. Int J Psychiatr Clin Pract 7: 107–112.

Nakagawa A, Watanabe N, Omori IM, et al. 2008. Efficacy and tolerabilityof milnacipran in the treatment of major depression in comparison withother antidepressants: a systematic review and meta-analysis. CNS Drugs22: 587–602.

Nicolini H, Bakish D, Duenas H, et al. 2008. Improvement of psychic andsomatic symptoms in adult patients with generalized anxiety disorder:examination from a duloxetine, venlafaxine extended-release andplacebo-controlled trial. Psychol Med 19: 1–10.

Ohman A. 2005. The role of the amygdala in human fear: automaticdetection of threat. Psychoneuroendocrinology 30: 953–958.

Papakostas GI. 2008. Tolerability of modern antidepressants. J Clin Psy-chiatry 69: 8–13.



Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. 2007. Areantidepressant drugs that combine serotonergic and noradrenergic mech-anisms of action more effective than the selective serotonin reuptakeinhibitors in treating major depressive disorder? A meta-analysis ofstudies of newer agents. Biol Psychiatry 62: 1217–1227.

Papp LA, Sinha SS, Martinez JM, Coplan JD, Amchin J, Gorman JM. 1998.Low-dose venlafaxine treatment in panic disorder. Psychopharmacol Bull34: 207–209.

Perkonigg A, Kessler RC, Storz S, Wittchen HU. 2000. Traumatic eventsand post-traumatic stress disorder in the community: prevalence, riskfactors and comorbidity. Acta Psychiatr Scand 101: 46–59.

Pollack M, Mangano R, Entsuah R, Tzanis E, Simon NM, Zhang Y. 2007.A randomized controlled trial of venlafaxine ER and paroxetine in thetreatment of outpatients with panic disorder. Psychopharmacology (Berl)194: 233–242.

Pollack MH, Worthington JJ, Otto MW, et al. 1996. Venlafaxine for panicdisorder: results from a double-blind, placebo controlled study. Psycho-pharmacol Bull 32: 667–670.

Preskorn SH. 2004. Milnacipran: a dual norepinephrine and serotoninreuptake pump inhibitor. J Psychiatr Pract 10: 119–126.

Puozzo C, Albin H, Vincon G, Deprez D, Raymond JM, Amouretti M.1998a. Pharmacokinetics of milnacipran in liver impairment. Eur J DrugMetab Pharmacokinet 23: 273–279.

Puozzo C, Pozet N, Deprez D, Baille P, Ung HL, Zech P. 1998b. Pharma-cokinetics of milnacipran in renal impairment. Eur J Drug MetabPharmacokinet 23: 280–286.

Puozzo C, Panconi E, Deprez D. 2002. Pharmacology and pharmacokineticsof milnacipran. Int Clin Psychopharmacol 17: 25–35.

Regier DA, Rae DS, Narrow WE, Kaelber CT, Schatzberg AF. 1998.Prevalence of anxiety disorders and their comorbidity with mood andaddictive disorders. Br J Psych Suppl 34: 24–28.

Ressler KJ, Nemeroff CB. 2000. Role of serotonergic and noradrenergicsystems in the pathophysiology of depression and anxiety disorders.Depress Anxiety 12: 2–19.

Rickels K, Pollack MH, Sheehan DV, Haskins JT. 2000. Efficacy ofextended-release venlafaxine in nondepressed outpatients with general-ized anxiety disorders. Am J Psychiatry 157: 968–974.

Rickels K, Mangano R, Khan A. 2004. A double-blind, placebo-controlledstudy of a flexible dose of venlafaxine ER in adult outpatients withgeneralized social anxiety disorder. J Clin Psychopharmacol 24: 488–496.

Roseboom PH, Kalin NH. 2000. Neuropsychopharmacology of venlafax-ine. Depress Anxiety 12: 20–29.

Rudolph RL. 2002. Achieving remission from depression with venlafaxineand venlafaxine extended release: a literature review of comparativestudies with selective serotonin reuptake inhibitors. Acta Psychiatr ScandSuppl 415: 24–30.

Rudolph RL, Entsuah R, Chitra R. 1998. A meta-analysis of the effects ofvenlafaxine on anxiety associated with depression. J Clin Psychophar-macol 18: 136–144.

Russell JM, Weisberg R, Fava M, Hartford JT, Erickson JS, D’Souza DN.2007. Efficacy of duloxetine in the treatment of generalized anxietydisorder in patients with clinically significant pain symptoms. DepressAnxiety 25: 1–11.

RynnM, Russell J, Erickson J, et al. 2008. Efficacy and safety of duloxetinein the treatment of generalized anxiety disorder: a flexible-dose, pro-gressive-titration, placebo-controlled trial. Depress Anxiety 25: 182–189.

Salzman C, Miyawaki EK, le Bars P, Kernhard TN. 1993. Neurobiologicbasis of anxiety and its treatment. Harv Rev Psychiatry 1: 197–206.

Saxena S, Rauch SL. 2000. Functional neuroimaging and the neuroanatomyof obsessive-compulsive disorder. Psychiatr Clin North Am 23: 563–586.

Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain J, Tourian KA.2007. A randomized, double-blind, placebo-controlled trial of desvenal-faxine succinate in the treatment of major depressive disorder. Int ClinPsychopharmacol 22: 338–347.

Shader RI, Greenblatt DJ. 1993. Use of benzodiazepines in anxiety dis-orders. N Eng J Med 328: 1398–1405.

Shilling A, Young-Sciame R, Leung L. 2005. Comparison of inhibitoryeffects of desvenlafaxine succinate, venlafaxine, SS duloxetine, parox-

etine, sertraline and bupropion on human cytochrome P450 activities.Poster presented at International Society for the Study of Xenobiotics,Maui, HI.

Shin LM, Rauch SL, Pitman RK. 2006. Amygdala, medial prefrontalcortex, and hippocampal function in PTSD. Ann N Y Acad Sci 1071:67–79.

Silverstone PH. 2004. Qualitative review of SNRIs in anxiety. J ClinPsychiatry 65: 19–28.

Smajkic A, Weine S, Duric-Bijedic Z, Boskailo E, Lewis J, Pavkovic I.2001. Sertraline, paroxetine and venlafaxine in refugee post traumaticstress disorder with depression symptoms. Med Arh 55: 35–38.

Smith D, Dempster C, Glanville J, Freemantle N, Anderson I. 2002. Efficacyand tolerability of venlafaxine compared with selective serotoninreuptake inhibitors and other antidepressants: a meta-analysis. Br JPsychiatry 180: 396–404.

Sopko MA Jr, Ehret MJ, Grgas M. 2008. Desvenlafaxine: another‘‘Me Too’’ Drug? (October) (CE). Ann Pharmacother 42: 1439–1446.

Stahl SM. 1998. Mechanism of action of selective serotonin reuptakeinhibitors. Serotonin receptors and pathwaysmediate mediate therapeuticeffects and side effects. JAD 51: 215–235.

Stahl SM. 1999. Why settle for silver, when you can go for gold? Responsevs. recovery as the goal of antidepressant therapy. J Clin Psychiatry 60:213–214.

Stahl SM, Entsuah R, Rudolph RL. 2002. Comparative efficacy betweenvenlafaxine and SSRIs: a pooled analysis of patients with depression.Biol Psychiatry 52: 1166–1174.

Stein MB, Pollack MH, Bystritsky A, Kelsey JE, Mangano RM. 2005.Efficacy of low and higher dose extended-release venlafaxine in gener-alized social anxiety disorder: a 6-month randomized controlled trial.Psychopharmacology (Berl) 177: 280–288.

Sugimoto Y, Tagawa N, Kobayashi Y, Hotta Y, Yamada J. 2007. Effectsof the serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipranon marble burying behaviour in mice. Biol Pharm Bull 30: 2399–2401.

Sultan A, Gaskell H, Derry S, Moore RA. 2008. Duloxetine for painfuldiabetic neuropathy and fibromyalgia pain: systematic review of random-ised trials. BMC Neurol 8: 29.

Tamminga CA. 2006. The anatomy of fear extinction. Am J Psychiatry 63:961.

Thase ME. 2008. Are SNRIs more effective than SSRIs? A review of thecurrent state of the controversy. Psychopharmacol Bull 41: 58–85.

Thase ME, Entsuah AR, Rudolph RL. 2001. Remission rates duringtreatment with venlafaxine or selective serotonin reuptake inhibitors.Br J. Psychiatry 179: 79.

Thase ME, Sloan DME. 2006. Venlafaxine. In Essentials of ClinicalPsychopharmacology, Chap. 11, Schatzberg AF, Nemeroff CB (eds).American Psychiatric Publishing, Inc.: Wahington, DC; 159–170.

Tourian KA, Ahmed S, Patroneva A, Zitek B, Graepel J, Pitrosky B. 2007.Improvement of anxiety symptoms in patients with major depressivedisorder treated with desvenlafaxine succinate: a pooled analysis. Posterpresented at APA Meeting, San Diego.

Ursano RJ, Bell C, Eth S, et al. 2004. Practice guideline for the treatment ofpatients with acute stress disorder and posttraumatic stress disorder. Am JPsychiatry 161: 3–31.

Van Ameringen M, Mancini C, Pipe B, Bennett M. 2004. Antiepilepticdrugs in the treatment of anxiety disorders: role in therapy. Drugs. 64(19): 2199–2220.

Werneke U, Northey S, Bhugra D. 2006. Antidepressants and sexualdysfunction. Acta Psychiatr Scand 114: 384–397.

Whalen PJ, Johnstone T, Somerville LH, et al. 2008. A functional magneticresonance imaging predictor of treatment response to venlafaxine ingeneralized anxiety disorder. Biol Psychiatry 63: 858–863.

Whiteside SP, Port JD, Abramowitz JS. 2004. A meta-analysis of functionalneuroimaging in obsessive-compulsive disorder. Psychiatry Res 132: 69–79.

Wise TN, Perahia DG, Pangallo BA, LosinWG,Wiltse CG. 2006. Effects ofthe antidepressant duloxetine on body weight: analyses of 10 clinicalstudies. Prim Care Companion J Clin Psychiatry 8: 269–278.

Wittchen HU, Hoyer J. 2001. Generalized anxiety disorder: nature andcourse. J Clin Psychiatry 62: 15–19.



Wittchen HU, Jacobi F. 2005. Size and burden of mental disorder in Europe:a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol15: 357–376.

Wu JC, Buchsbaum MS, Hershey TG, Hazlett E, Sicotte N, Johnson JC.1991. PET in generalized anxiety disorder. Biol Psychiatry 29: 1181–1199.

Yariyura-Tobias JA, Neziroglu FA. 1996. Venlafaxine in obsessive-com-pulsive disorder. Arch Gen Psychiatry 53 (7): 653–654.

Yonkers KA, Bruce SE, Dyck IR, Keller MB. 2003. Chronicity, relapse, andillness–course of panic disorder, social phobia, and generalized anxietydisorder: findings in men and women from 8 years of follow-up. DepressAnxiety 17: 173–179.

Zwanzger P, Eser D, Rupprecht R. 2007. Anticonvulsants in the treatmentof anxiety–an alternative treatment option? Nervenarzt 78 (11): 1274–1282.



Copyright of Human Psychopharmacology: Clinical & Experimental is the property of John Wiley & Sons Ltd.

1996 and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright

holder's express written permission. However, users may print, download, or email articles for individual use.

Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review...

Documents

Transcript of Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review...