Venlafaxine in the treatment of anxiety disorders

Venlafaxine extended-release (Effexor XR, Wyeth-Ayerst Co.) is a novel, dual acting serotonin-norepinephrine reuptake inhibitor antidepressant, which inhibits the synaptic reuptake of both serotonin and norepinephrine. Controlled trials have demonstrated the efficacy and safety of venlafaxine in the treatment of anxiety disorders including social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, panic disorder and obsessive-compulsive disorder. Generally well-tolerated with side effects that usually abate with continued treatment, venlafaxine is an important alternative to the selective serotonin reuptake inhibitors for patients with anxiety disorders.     

Treatment of anxiety disorders with venlafaxine XR

When venlafaxine was introduced in 1994, it was the first of the newer generation antidepressants to be classified as a serotonin norepinephrine reuptake inhibitor (SNRI). An extended release (XR) formulation of venlafaxine, introduced in 1997, subsequently received regulatory approval for treatment of three anxiety disorders: generalized anxiety disorder, social anxiety disorder and panic disorder. Although less extensively studied, venlafaxine XR also appears to have efficacy for two other anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder. In contrast to the treatment of depression, for which meta-analyses suggest an efficacy advantage relative to selective serotonin reuptake inhibitors (SSRIs), evidence of differential efficacy has not yet been established for any of the anxiety disorders. The overall tolerability profile of venlafaxine XR is generally comparable to that of the SSRIs, although there is greater incidence of noradrenergically mediated side effects (i.e., dry mouth and constipation), as well as a dose-dependent risk of treatment-emergent high blood pressure. Concerns about safety in overdose have also recently emerged. Despite these caveats, venlafaxine XR is an effective and generally well-tolerated option for treatment of anxiety disorders.     

Efficacy, safety, and tolerability of venlafaxine XR in generalized anxiety disorder

Generalized anxiety disorder (GAD) is a common and chronic disorder with a low rate of spontaneous remission. A complication in treatment selection is the high rates of co-morbid major depressive disorder in this population. A number of treatments exist to treat GAD. The most recent medication to gain an indication for GAD is venlafaxine XR, a serotonin/norepinephrine reuptake inhibitor that is also approved for the treatment of major depressive disorder. More than 2,000 patients with GAD have been studied in outpatient trials of venlafaxine XR with demonstrated efficacy, tolerability and safety of this compound. This article reviews these studies, both short term and longer (6 month) continuation trials. The response to venlafaxine XR in this population, combined with good tolerability, makes this agent an appropriate first-line medication for GAD. In general, treatment with antidepressants, though associated with a longer onset of action than benzodiazepines, does not produce physiological dependency, and is useful in a patient population with a high prevalence of mood disorders.     

Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity.

BACKGROUND: Though selective serotonin reuptake inhibitors have revolutionized the field of psychiatry with demonstrated efficacy in affective and anxiety disorders with minimal side effects, norepinephrine-serotonin reuptake inhibitors may provide efficacy similar to tricyclic antidepressants without the adverse side effects associated with tricyclic antidepressants. METHODS: The affinity and selectivity of milnacipran, duloxetine, venlafaxine, citalopram, amitriptyline, and nortriptyline were determined for the human serotonin, norepinephrine, and dopamine transporters. RESULTS: Both milnacipran and duloxetine were potent inhibitors of serotonin and norepinephrine uptake. Unlike duloxetine and venlafaxine, milnacipran appears serotonin transporter selective in binding (ratio = 2.61) and norepinephrine transporter selective in uptake (ratio =.45). CONCLUSIONS: Milnacipran's binding and uptake inhibition profile more closely resembles that of the tricyclic antidepressants than that of duloxetine. Whether these differences observed in vitro manifest themselves in vivo is not clear.     

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders.

In this report, recommendations for the pharmacological treatment of anxiety and obsessive-compulsive disorders are presented, based on available randomized, placebo- or comparator-controlled clinical studies. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for panic disorder. Tri2-cyclic antidepressants (TCAs) are equally effective, but they are less well tolerated than the SSRIs. In treatment-resistant cases, benzodiazepines like alprazolam may be used when the patient does not have a history of dependency and tolerance. Due to possible serious side effects and interactions with other drugs and food components, the irreversible monamine oxidase inhibitor (MAOI) phenelzine should be used only when first-line drugs have failed. In generalised anxiety disorder, venlafaxine and SSRIs can be recommended, while buspirone and imipramine may be alternatives. For social phobia, SSRIs are recommended for the first line, and MAOIs, moclobemide and benzodiazepines as second line. Obsessive-compulsive disorder is best treated with SSRIs or clomipramine.     

Management of psychiatric comorbidity in fibromyalgia

Fibromyalgia is a chronic musculoskeletal pain condition of unknown etiology that predominantly affects women. Lifetime mood and anxiety disorders are common in patients with fibromyalgia and affect the course and severity of fibromyalgia. Recent fibromyalgia clinical trials have included clinical assessments to identify comorbid psychiatric disorders and determine the impact of comorbidity on treatment response. Options for the treatment of fibromyalgia patients with comorbid major depressive disorder or anxiety disorders include antidepressants with dual effects on serotonin and norepinephrine (eg, venlafaxine, duloxetine), which reduce pain in patients with fibromyalgia and have antidepressant and anxiolytic activity. Other possible treatments for anxiety or sleep disturbances associated with fibromyalgia include the alpha-2-delta ligands (eg, pregabalin, gabapentin) that reduce pain in fibromyalgia patients, have anxiolytic effects, and enhance slow-wave sleep. Antidepressants or alpha-2-delta ligands should be combined with established mood stabilizers in patients with comorbid fibromyalgia and bipolar disorder. There is also evidence to support exercise and cognitive-behavioral therapy in the treatment of fibromyalgia and mood or anxiety disorders. Many patients would likely benefit from combinations of pharmacologic and nonpharmacologic treatments.     

Delayed pharmacological effects of antidepressants

Although antidepressants may not be primary mood stabilizers, they are efficacious in the prophylaxis of recurrent depressive illnesses, as well as in the treatment of acute episodes. Pharmacological effects that may contribute to the prophylactic effects of these drugs are not understood. Studies have been carried out in which antidepressants have been given to laboratory animals, such as rats, for periods of up to 3-4 weeks. Data obtained in such studies are thought to be important for their beneficial effects in depressive episodes, but also may be relevant to their prophylactic effects. Results are presented showing that when selective inhibitors of serotonin or norepinephrine uptake are given for such time periods, they still produce selective effects on serotonergic or noradrenergic parameters. For example, long-term administration of selective norepinephrine reuptake inhibitors causes a down-regulation of beta(1) adrenoceptors. Selective serotonin reuptake inhibitors do not produce this effect. Long-term administration of selective serotonin reuptake inhibitors causes down-regulation of the serotonin transporter, but not the norepinephrine transporter. In contrast, selective norepinephrine reuptake inhibitors down-regulate the norepinephrine transporter but not the serotonin transporter. Substantial loss of serotonin transporter binding sites takes 15 days to occur and is accompanied by a marked reduction of serotonin transporter function in vivo.     

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety,Obsessive-Compulsive and Posttraumatic Stress Disorders

Summary

In this report, recommendations for the pharmacological treatment of anxiety and obsessive-compulsive disorders are presented, based on available randomized, placebo-or comparator-controlled clinical studies.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for panic disorder. Tri²-cyclk antidepressants (TCAs) are equally effective, but they are less well tolerated than the SSRIs. In treatment-resistant cases, benzodiazepines like alprazolam may be used when the patient does not have a history of dependency and tolerance. Due to possible serious side effects and interactions with other drugs and food components, the irreversible monamine oxidase inhibitor (MAOI) phenelzine should be used only when first-line drugs have failed. In generalised anxiety disorder, venlafaxine and SSRIs can be recommended, while buspirone and imipramine may be alternatives. for social phobia, SSRIs are recommended for the first line, and MAOIs, moclobemide and benzodiazepines as second line. Obsessive-compulsive disorder is best treated with SSRIs or clomipramine.     

Psychopharmacologic treatment of children and adolescents with anxiety disorders

Over the last decade, psychopharmacologic treatments for pediatric anxiety disorders have been developed and increasingly subjected to randomized, controlled trials. The authors summarize the data concerning the use of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), atypical anxiolytics, and benzodiazepines. The extant data suggest that SSRIs--both as monotherapy and when combined with psychotherapy--are effective in the treatment of pediatric anxiety disorders. In addition, some TCAs and SNRIs are effective. However, randomized controlled trials do not suggest efficacy for benzodiazepines or the atypical anxiolytic, buspirone, for children and adolescents with anxiety disorders.     

Child and adolescent depression: short-term treatment effectiveness and long-term opportunities

As with adult major depressive disorder (MDD), child and adolescent MDD is characterized as a common, chronic and recurrent disorder. It is also associated with short- and long-term functional impairment, morbidity, and mortality. Effective treatments, both psychotherapeutic and pharmacotherapeutic, are available for the short-term treatment and management of youth with MDD. However, to date, there are no data on the long-term treatment and management of children and adolescents with MDD and how long-term treatment may affect the outcomes of either high-risk or already affected youth. Understanding the long-term consequences of MDD during youth is as important as understanding how to treat a single episode of depression. Available data on the pharmacotherapeutic and psychotherapeutic options are discussed. In general, tricyclic antidepressants (TCAs) are not as effective for the treatment of youth with MDD as adults with MDD. The selective serotonin reuptake inhibitors (SSRIs) have been shown to be effective in children and adolescents with MDD and non-obsessive compulsive anxiety disorders. The serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine XR, has been shown to be effective for the treatment of generalized anxiety disorder in children and adolescents. Understanding the long-term clinical consequences of depressive disorders in youth may provide opportunities for better intervention across the clinical course of illness. Early recognition, diagnosis and adequate treatment of 'high-risk' youth with subsyndromal depressive symptoms, treatment of acute episodes of depression to prevent 'kindling', and aggressive prophylaxis have the potential to improve the mental health of youth throughout their lives.     

Emerging treatments for child and adolescent social phobia: a review

Social anxiety disorder, or social phobia (SP), is an anxiety disorder characterized by excessive fear of exposure to situations that involve potential scrutiny by others. SP is a common psychiatric problem in children and adolescents, often presenting with comorbid anxiety and mood disorders. Although the onset of SP is typically in late childhood or early adolescence, most afflicted individuals go undiagnosed for years, not seeking treatment until adulthood. First-line treatments for SP in adults support the use of pharmacotherapy and cognitive behavioral therapy. There is new and emerging data in youths with SP to support the use of similar treatments. This paper will review the clinical characteristics, epidemiology, and treatment of SP in youths. Current investigations using selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, benzodiazepines, and monoamine oxidase inhibitors in youths will be reviewed. Several studies on the use of cognitive behavioral therapy in youths will also be examined. Practical guidelines for clinicians who treat children and adolescents are also presented.     

Painful physical symptoms in depression: a clinical challenge

Painful physical symptoms are common elements within mood disorders and provide a therapeutic challenge when such patients attribute their pain to causes other than the mood disorder. These somatic presentations may lead to under-diagnosis and inappropriate treatment of patients with mood disorders. Antidepressant agents that inhibit both serotonin and norepinephrine reuptake effectively remit mood disorders, thereby providing relief of painful physical symptoms often associated with these disorders. They may also provide analgesia for neuropathic pain, such as that caused by diabetic neuropathy, which are associated with mood disorders. Newer generation dual acting antidepressants such as duloxetine and venlafaxine offer a well-tolerated and safe alternative to tricyclics. Concurrent with medication and management, the physician must educate the patient about the nature of both depressed mood and painful physical states that are augmented by and inherent in the depressive disorders. This mini review addresses the problems inherent to the treatment of painful physical symptoms in depression.     

Comorbidity of mood and anxiety disorders

This article reviews data on the prevalence of panic, social phobia, generalized anxiety, and posttraumatic stress disorder, and research documenting the comorbidity of these disorders with major depression (MDD). These anxiety disorders are frequently comorbid with MDD, and 50-60% of individuals with MDD report a lifetime history of one or more of these anxiety disorders. The anxiety disorders are also highly correlated with one another, and approximately one-quarter to one-half of individuals with each of the anxiety disorders report a lifetime history of an alcohol or substance use disorder. Anxiety disorders rarely exist in isolation, with several studies reporting that over 90% of individuals with anxiety disorders have a lifetime history of other psychiatric problems. Implications for research are discussed, including the potential benefit of using combined categorical and dimensional rating scale approaches in future genetic, biochemical, neuroimaging, and treatment studies. The clinical implications of the findings are also discussed, and the results of recent clinical trials summarized. Available data suggests selective serotonin reuptake inhibitors are the first-line pharmacological treatment for these disorders, and that newer serotonin and norepinephrine reuptake inhibitors show significant promise, especially for comorbid cases. Comorbidity among depression and anxiety disorders is associated with greater symptom severity, and a considerably higher incidence of suicidality. Increased public awareness about these disorders and the availability of effective treatments is sorely needed.     

Antidepressants in the treatment of fibromyalgia

Fibromyalgia syndrome is a chronic disease of widespread and debilitating pain whose cause is unknown and whose risk factors are poorly understood. It is often comorbid with rheumatoid and other pain disorders as well as psychiatric disorders such as anxiety and depression. Although they are not officially approved for this indication, antiepileptics and antidepressants are often used to treat fibromyalgia. The tricyclic antidepressants (TCAs), particularly amitriptyline, are among the most common treatment strategies. Because of the poor tolerability of the tricyclics, the newer antidepressants have been widely tested in fibromyalgia. The selective serotonin reuptake inhibitors (SSRIs) and the reversible monoamine oxidase inhibitors do not seem to be particularly helpful. The serotonin and norepinephrine reuptake inhibitors (SNRIs), duloxetine and milnacipran, on the other hand, have been shown in placebo-controlled trials to offer significant relief to patients suffering from fibromyalgia. Although no direct comparative studies have been performed, these compounds appear to be as effective as the TCAs but much better tolerated. The effectiveness of the SNRIs as well as other dual acting antidepressants, such as mirtazapine, but not the SSRIs, implies that a dysfunction of both serotonin and norepinephrine neurotransmission probably exists in fibromyalgia. The effectiveness of antidepressants appears to be independent of their effect on comorbid depression.     

Management of panic disorder

Selective serotonin reuptake inhibitors are the first-line treatment for panic disorder. They are effective and well tolerated. Although tricyclic antidepressants are equally effective, they are less well tolerated than the selective serotonin reuptake inhibitors. Monoamine oxidase inhibitors can be efficacious but have a range of unwanted effects that preclude their use as first-line treatments. Benzodiazepines should be reserved for short-term use and for treatment-resistant patients who do not have a history of dependence and tolerance. Also, they can be combined with selective serotonin reuptake inhibitors in the first weeks of treatment to tide the patient over before the onset of the response. Cognitive behavioral therapy is the psychologic treatment of first choice. The methods of combining drug and nondrug treatments need careful and thorough exploration.     

The brain galanin receptors: targets for novel antidepressant drugs

Our present view that the mood disorders involve dysfunction of monoaminergic system is a result of important clinical and preclinical observations over the past 40 years. The therapeutic efficacy of drugs such as the tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and lately of SNRIs (serotonin and norepinephrine reuptake inhibitors) helped to shape our view that mood regulation involves the monoaminergic systems in some way. It is thus little surprising when the neuropeptide, galanin, is discovered to coexist with norepinephrine (NE) in locus coeruleus (LC) neurons and with serotonin (5-HT) in the dorsal raphe nucleus (DRN) neurons, a link between galanin mediated signaling and mood regulation is sought. Galanin receptors are expressed in brain structures that are involved in the regulation of mood such as frontal cortex, amygdala, hypothalamus, LC, DRN and hippocampus. It is almost an accident of research fate that the potent effects of galanin on cognitive performance and seizure threshold have led galanin research to focus on the hippocampus where the neuropeptide is present in cholinergic and noradrenergic afferents and where the receptor density is much lower than in the monoaminergic nuclei. Hopefully it is not too late to report on the recent inroads into the roles of galanin and of galanin receptor subtypes 2 and 3 (GalR2 and GalR3) in mood regulation in animal models as well as in human patients with major depression. A body of existing data suggests that GalR2 signaling leads to antidepressant-like, anticonvulsant and neurogenesis-promoting effects, a spectrum of activities that are commonly associated with efficacious antidepressants. Similarly, GalR3 antagonists exhibit anxiolytic and antidepressant-like activity, another clinically useful combination for the treatment of mood disorders. Since both GalR2 and GalR3 are G-protein coupled receptors (GPCRs), a favorite target class for drug development, we believe that the pace of developing galaninergic antidepressants will increase significantly from now on.     

The role of duloxetine in the treatment of anxiety disorders

Anxiety disorders (ADs) are the most common type of psychiatric disorders, with a mean incidence of 18.1% and a lifetime prevalence of 28.8%. Pharmacologic options studied for treating ADs may include benzodiazepines, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and specific serotonergic drug (NaSSA) and dual-reuptake inhibitors of serotonin and norepinephrine (SNRIs). In this context, the development of SNRIs (venlafaxine and duloxetine) has been particularly useful. As a dual-acting intervention that targets two neurotransmitter systems, these medications would appePar promising for the treatment of ADs. The purpose of this review was to elucidate current facts and views about the role of duloxetine in the treatment of ADs. In February 2007, duloxetine was approved by FDA for the treatment of generalized anxiety disorder (GAD). The results of trials evaluating the use duloxetine in the treatment of GAD are supportive on its efficacy even if further studies on long-term use are needed. Apart from some interesting case reports, no large studies are, to date, present in literature about duloxetine and other ADs such as panic disorder, social anxiety disorder, obsessive-compulsive disorder and post-traumatic stress disorder. Therefore, the clinical efficacy and the relative good tolerability of duloxetine may be further investigated to widen the therapeutic spectrum of ADs.     

Dose-response relationship of recent antidepressants in the short-term treatment of depression

Antidepressant drugs are widely recommended for the treatment of depressive disorders, and finding the "right dose for the right patient" is an important issue. Whatever antidepressant is prescribed, a proportion of adult patients with major depression fail to respond satisfactorily to adequate first-line treatment. A frequent strategy for patients with insufficient response to an initial antidepressant dose is to increase the dose. This review is about this strategy, ie, the possible benefits of prescribing higher doses of recent antidepressants. The results show that a flat dose-response curve is a class phenomenon for selective serotonin reuptake inhibitors (SSRIs), according to randomized, controlled, fixed-dose clinical trials. For the serotonin and noradrenaline reuptake inhibitors (SNRIs), the strategy of dose increase may be relevant for venlafaxine, in order to increase the number of responders. Thus, the subgroup of patients for whom high doses of SSRIs could be useful remains to be defined.     

Affective disorder and epilepsy comorbidity: implications for development of treatments, preventions and diagnostic approaches.

Concepts pertaining to affective disorder and epilepsy comorbidity are contributing appreciably to improvements in patient care. Several antiepileptic treatments have become important components of the management of bipolar affective disorder. In contrast, little progress has emerged in developing clinical applications of the anticonvulsant properties of the antidepressants in the treatment of the epilepsies. The slow onset of action of the antidepressants remains a major impediment to fully effective treatment of depressive episodes. Nevertheless, studies from experimental epileptology demonstrate that the anticonvulsant effects of the antidepressants occur rapidly and as a consequence of noradrenergic and/or serotonergic activation. These studies also demonstrate that adequate initial doses of the antidepressants are essential to rapid onset of anticonvulsant action. Pharmacokinetically valid loading dose paradigms are seemingly avoided with antidepressant drugs in humans because of potential toxicities and/or patient unacceptability. However, substantial progress has been made in reducing the adverse effect liability of the antidepressants. No longer is convulsive liability considered to stem from the therapeutic mechanisms of the anti-depressants. Rather, noradrenergic and serotonergic influences have demonstrable anticonvulsant properties. Other side effects may also be separable from the anticonvulsant and antidepressive effects of antidepressive treatments. The concept that the protracted process of antidepressant-induced beta-noradrenergic down-regulation is an essential prelude to the onset of mood benefit is no longer a sustainable premise. Nevertheless, increasing evidence underlies the possibility that knowledge of serotonergic and noradrenergic regulatory processes can be used to design strategies that will hasten the onset of antidepressive action. Similar optimism pervades efforts to determine the possibility that dual inhibition of serotonin and norepinephrine transporters will hasten onset of antidepressive action. Moreover, because noradrenergic and serotonergic systems are determinants of predisposition to seizures and to dysfunctional affective episodes, augmentation strategies may also be applicable to the use of antidepressant drugs in epilepsy and to the use of antiepileptic drugs such as carbamazepine in mood disorders. Recent studies have demonstrated that, in part, the therapeutic effectiveness of carbamazepine may stem from its marked capacity to elevate serotonin concentrations in the extracellular fluid of the brain via mechanisms that differ from those of the membrane reuptake inhibitors. Evidence suggests that the epilepsies and affective disorders may arise from a multiplicity of neurobiological abnormalities. A disorder in one individual may arise via different mechanisms than a phenomenologically similar disorder in another individual. Thus, diagnostic tools are needed to make mechanistic distinctions among individuals so that treatments can be appropriately developed and selected. In terms of epileptogenesis and affective disorder progression, neuroprotective paradigms for one individual may differ from those needed for another. Moreover, diagnostic technologies that are adequate to detect genetically and/or experientially determined vulnerability before the onset of a seizure or dysfunctional affective episode may be valuable steps toward achieving goals of prevention.     

Effectiveness of paroxetine in the treatment of obsessive-compulsive disorders

Clomipramine ushered in a new age of pharmacotherapy for obsessive-compulsive disorders, and it also facilitated our understanding of the biological aspects of obsessive-compulsive disorder, focusing on the serotonergic systems. The introduction of selective serotonin reuptake inhibitors has led to great progress in the pharmacological study of obsessive-compulsive disorder based on the serotonin hypothesis. Currently, selective serotonin reuptake inhibitors are positioned as a first-line drug of obsessive-compulsive disorder pharmacotherapy in the various guidelines and algorithms. Among six different selective serotonin reuptake inhibitors (paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram, escitalopram) that are available worldwide, paroxetine has the broadest treatment spectrum and promises great benefits not only for obsessive-compulsive disorder patients, but also for those with comorbid depression and/or various kinds of anxiety disorders. This paper presents several clinical trials of paroxetine carried out, and discusses and reviews the therapeutic strategies for obsessive-compulsive disorder.