Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes

Irritable bowel syndrome (IBS) is characterized by abdominal pain associated with disordered defecation, which may include urgency and altered stool frequency. Visceral pain syndromes, including IBS, may be effectively treated by a variety of therapies that modulate the interactions between the central and enteric nervous systems. Clinical observations and preliminary data suggest that antidepressants may be efficacious for the treatment of these syndromes. The tricyclic antidepressants (TCAs) have been utilized most extensively in this area, but there is a need for more rigorous efficacy data. Serotonin, an important neurotransmitter in both the central and enteric nervous systems, modifies both motility and sensation in the gut. Recognition of the importance of serotonin in digestive motility and sensation has sparked interest in the use of agents that modify serotonergic transmission in visceral pain syndromes. Pharmacological therapeutics that modulate the biological amines (serotonin, norepinephrine, dopamine and catecholamines) both peripherally and within the central nervous system may offer more effective therapies for these disorders. The selective serotonin reuptake inhibitors are commonly used in clinical practice, but more rigorous, controlled studies are needed to determine their effects beyond the treatment of psychiatric comorbidity. The newer generation antidepressants may provide additional insight into the pathophysiology of the brain-gut interactions and their relationship to functional bowel disorders, providing new therapeutic interventions.     

Antidepressants as analgesics

Depression is a common accompaniment of pain, particularly when pain is unremitting. The use of a variety of antidepressant medications is associated with pain reduction, an effect that is independent of the mood-enhancing qualities of these drugs. This pain relief is a consequence of a wide variety of actions of antidepressants on the neuroregulatory mechanisms associated with pain perception and transmission.The older tricyclic antidepressants (TCAs) and the newer 'balanced' reuptake inhibitors (such as duloxetine) seem to be more efficacious in terms of providing pain relief than the selective serotonin reuptake inhibitors (SSRIs). Unfortunately, adverse effects are not uncommon during antidepressant use, particularly with TCAs. It is now becoming apparent that TCAs can have an analgesic effect when applied topically and that this effect is produced by peripheral mechanisms rather than systemic uptake.Antidepressants remain a major therapeutic tool in the management of chronic pain.     

Neuronal and immunological basis of action of antidepressants in chronic pain – clinical and experimental studies

The current knowledge of the pharmacological actions of the tricyclic antidepressants (TCAs) has slowly evolved through their over 40-year history. Chronic pain represents one of the most important public health problems, and antidepressants are an essential part of the therapeutic strategy in addition to classical analgesics. This article reviews the available evidence on the efficacy and safety of antidepressants in chronic pain conditions; namely, headaches, low back pain, fibromyalgia, cancer pain and especially neuropathic pain. TCAs are traditionally the main type of depression medication used to treat chronic pain. Recently, new antidepressants were introduced into clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs that are effective for chronic pain belong to the tetracyclic antidepressants (TeCAs) group (amoxapine, maprotiline), the serotonin and noradrenaline reuptake inhibitors (SNRIs) group (duloxetine, venlafaxine, milnacipran) and the atypical antidepressants group (bupropion, trazodone, mirtazapine, nefazodone). In this review, we present the available publications on TCAs (amitriptyline, doxepin, imipramine, desipramine, nortriptyline), TeCAs (amoxapine, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine, venlafaxine, milnacipran) and atypical antidepressants (bupropion) for the treatment of neuropathic pain.We also review analgesics acting as both opioid receptor agonists and also acting as aminergic reuptake inhibitors. Existing data are insufficient to conclude which of these new classes of antidepressants has the best clinical profile and will be the most effective in the treatment of neuropathic pain; in addition, a lower incidence of side effects should be considered. Increased experimental and translational research is a key for further improvement of the treatment of chronic pain with antidepressants. However, evidence from basic science is needed to improve our understanding of the mechanisms of action and their possible pharmacodynamic interactions.     

Treating mood disorders during pregnancy: safety considerations.

Mood disorders in pregnancy may have a negative effect on self care and pregnancy outcome that affects the mother directly and the child indirectly. Thus, some women may require pharmacological treatment. Pharmacotherapy of mood disorders during pregnancy implies specific considerations.This paper presents an updated review of available studies on the treatment of mood disorders and present knowledge on teratogenicity, neonatal effects and long-term neurobehavioural effects for the different psychotropic drugs, including treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), other antidepressants, benzodiazepines, lithium, carbamazepine/valproic acid, lamotrigine and novel antipsychotics. However, the existing knowledge on the use of antidepressants and mood stabilising agents during pregnancy is hampered by a lack of results from randomised controlled trials.SSRIs and TCAs have not been associated with an increased risk of major malformations, but poor neonatal adaptation has been described. Benzodiazepines used in the first trimester have been associated with orofacial clefts. Mood stabilisers such as lithium, carbamazepine and valproic acid (sodium valproate) are associated with an increased risk of fetal malformations. Both benzodiazepines and lithium may cause adaptation problems in the newborn. In utero exposure to novel antipsychotics has not been associated with congenital malformations; however, the data are still limited. The knowledge about long-term neurobehavioural effects in the offspring is still limited for all agents and requires further investigation. Possible adverse effects of fetal exposure must be balanced against the adverse effects of an untreated maternal mood disorder.     

Drug treatment options for irritable bowel syndrome: managing for success

Irritable bowel syndrome (IBS) is a functional gut disorder the diagnosis of which is based on clinical symptoms as set forth by the Rome criteria. As the population ages, especially with the population of patients >75 years of age expanding greatly over the next 10 years, IBS is becoming one of the most common diseases of the elderly. Thus far, developing treatment strategies for patients with IBS has been difficult because of the lack of pharmacological targets and the wide range of symptomatology. Additionally, demonstration of a therapeutic benefit is difficult in the presence of a high placebo response observed regardless of the therapy employed. Fibre, antidiarrhoeals and antispasmodics all play some role in the symptomatic treatment of IBS. With the evolution of IBS as a disorder of visceral hypersensitivity, new drugs have been developed that target the enteric nervous system. Tricyclic antidepressants (TCAs) have been found to target the enteric neurons and play a role in pain modulation. Currently, the TCAs are recommended only for severe cases of IBS pain. The newest class of drugs to be approved for use in IBS are the serotonin (5-hydroxytryptamine; 5-HT) antagonists. Specifically, the 5-HT3 receptor antagonists have been shown to decrease symptoms in female patients with IBS. A related class of drugs, the 5-HT4 receptor agonists, is being developed for the treatment of constipation-predominant IBS. Further investigation into the role of spinal afferent neurons in visceral hypersensitivity is at the forefront of IBS research. Several experimental drug therapies for IBS are also discussed in this review including N-methyl-D-aspartate receptor antagonists, neurokinin-1 receptor antagonists, octreotide, clonidine and the selective M3 receptor antagonist, zamifenacin.     

Remission,dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials

ABSTRACT

Objective: To summarize remission rates and dropouts due to adverse drug reactions (ADRs) or lack of efficacy (LoE) of serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin-reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs) in treating major depressive disorder.

Methods: We searched MEDLINE, EMBASE, IPA, and the Cochrane International Library from 1980–2005. Meta-analysis summarized outcomes from head-to-head randomized clinical trials comparing ≥ 2 drugs from three antidepressants classes (SNRIs, and/or SSRIs, and/or TCAs) followed by ≥ 6 weeks of treatment. Remission was a final Hamilton Depression Rating Scale (HAMD) score ≤ 7 or Montgomery-Åsberg Depression Rating Scale (MADRS) ≤ 12. Intent-to-treat data were combined across study arms using random effects models, producing point estimates with 95% confidence intervals.

Results: We obtained data from 30 arms of 15 head-to-head trials with 2458 patients. SNRIs had the highest ITT remission rate (49.0%), then TCAs (44.1%), and SSRIs (37.7%) (?p > 0.05 for SNRIs versus TCAs; p < 0.001 for TCAs versus SSRIs and SNRIs versus SSRIs). When categorized as inpatients (?n = 582) and outpatients (?n = 1613), SNRIs had the highest remission rates (52.0% for 144 inpatients and 49.3% for 559 outpatients). SNRIs had lowest overall dropouts (26.1%), followed by SSRIs (28.4%), and TCAs (35.7%). Dropouts due to ADRs and LoE were 10.3% and 6.2% for SNRIs, 8.3% and 7.2% for SSRIs, and 19.8% and 9.9% for TCAs, respectively (?p > 0.05 for ADR dropouts only). One limitation was the inclusion of only venlafaxine‐XR; results may not be the same for immediate release forms. In addition, few studies reported remission rates.

Conclusions: SNRIs had the highest efficacy remission rates (statistically significant for inpatients and outpatients), and the lowest overall dropout rates, suggesting clinical superiority in treating major depression.     

Panic Disorder—a Condition for Life? Treatment Issues

Panic disorder is a readily diagnosed, chronic condition which has received substantial attention since its recognition as a distinct condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III (American Psychiatric Association, 1980). Effective anti-panic therapy should show efficacy in reducing the frequency of panic attacks and associated symptomology, and be well tolerated. Benzodiazepines have a rapid onset of action, but have disadvantages of dependence and withdrawal problems and are thus less suitable for long-term use. Since depression occurs as a comorbid condition in 60 per cent of patients with panic disorder, the use of antidepressants is a logical choice. The first-generation monoamine oxidase inhibitors are little used in panic disorder, since they present a major problem of a potential hypertensive crisis, particularly when ingested with tyramine. Tricyclic antidepressants (TCAs), such as imipramine and clomipramine, are widely used and are effective but they are not well tolerated. The TCAs appear to exert their anti-panic effect via the serotonin reuptake pathway. Selective serotonin reuptake inhibitors (SSRIs) do not have anti-cholinergic effects or act on the noradrenergic system, thus there is a clear pharmacological rationale for believing that SSRIs should be as effective as TCAs in panic disorder and be better tolerated. Indeed, the SSRI paroxetine is as effective as clomipramine in panic disorder but has an improved tolerability profile; paroxetine is the only agent of its class licensed as a treatment for panic disorder. © 1997 John Wiley & Sons, Ltd.     

Section Review Central & Peripheral Nervous Systems: New antidepressant agents: Recent pharmacological developments leading to improved efficacy

The disadvantages of the standard tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), in terms of side-effects and fatal overdose, led to the development and release of seven new antidepressants in the USA in the past eight years with approximately another ten in various stages of development. This paper will focus on how recent advances in biochemistry and kinetics have led to improved efficacy. In particular, the more specific 5-HT agents appear effective for ‘typical’ depression and pain; the less specific ones for depression associated with obsessive-compulsive disorder. The selective serotonin reuptake inhibitors (SSRIs) are particularly suited for treatment of depression associated with diabetes mellitus; the serotonin and norepinephrine reuptake inhibitor (SNRI), venla-faxine, for resistant depression; and bupropion, for atypical depression. The serotonin receptor modulator (SRM), nefazodone, in contrast, is particularly suited for the treatment of depression associated with insomnia because of its combined SSRI and post-synaptic 5-HT_2A/C receptor antagonist effects. In terms of kinetics, important factors include, particularly: elimination half-lives, linearity of kinetics, therapeutic blood levels, effects on hepatic microen-zymes, and effects on memory and alertness. Discussion of these seven antidepressants is followed by a brief review of knowledge concerming other potential antidepressants in development.     

Specific serotonin and noradrenaline reuptake inhibitors (SNRIs). A review of their pharmacology,clinical efficacy and tolerability

Considerable progress has been made in improving the tolerability of antidepressant drugs. The classical tricyclic antidepressants (TCA) are still, however, the standard for efficacy. The selective serotonin reuptake inhibitors are better tolerated that the tricyclics, but their efficacy in major depression is, at best, equivalent to the earlier compounds and probably inferior in certain cases. Recently a new class of antidepressants has been developed that inhibit selectively the reuptake of both serotonin and noradrenaline with no affinity for the receptors responsible for the adverse effects of the TCAs. These compounds are referred to as the specific serotonin and noradrenaline reuptake inhibitors or SNRIs. This article reviews the pharmacological and clinical characteristics of the two principal compounds of this class, milnacipran (Ixel®) and venlafaxine (Effexor®). This new class of antidepressants, as represented by these two compounds, presents an efficacy comparable to TCAs with a more benign side-effect profile. Certain trials suggest that they may have efficacy superior to SSRIs, especially in more severe depression, with a tolerability which is globally similar. This class therefore appears to offer a potential useful addition to the therapeutic arsenal of antidepressant drugs. © 1998 John Wiley & Sons, Ltd.     

A review of SSRIs and SNRIs in neuropathic pain

Importance of the field: Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) are becoming increasingly used in the treatment of neuropathic pain and fibromyalgia. However, they are not without adverse effects and their efficacy has not been clear because of conflicting evidence.

Areas covered in this review: We have examined the current evidence on the efficacy of SSRIs and SNRIs in the treatment of neuropathic pain and fibromyalgia. Relevant randomized, placebo-controlled studies were identified through a MEDLINE search of English-language literature from January 1990 to December 2009.

What the reader will gain: The evidence for efficacy of SSRIs in the treatment neuropathic pain is moderate at best. However, SNRIs, venlafaxine and duloxetine have been shown to be effective in the treatment of painful diabetic neuropathy and polyneuropathy. With fibromyalgia, both SSRIs (fluoxetine and paroxetine) and SNRIs (duloxetine and milnacipran) have been shown to improve pain relief, function and quality of life.

Take home message: SSRIs and SNRIs may be considered in the treatment of neuropathic pain if treatment with tricyclic antidepressants and anticonvulsants fails, or if there are contraindications to these drugs. There is also sufficient evidence to indicate that SNRIs are effective in the treatment of fibromyalgia and may be considered early in the treatment of fibromyalgia.     

Agomelatine in treating generalized anxiety disorder

Introduction: Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a lifetime prevalence of 4.3 – 5.9% in the general population. Many drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines, antidepressants (selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants), anticonvulsants, azapirones, antihistamines, atypical antipsychotics, complementary/alternative medicine, psychotherapy and Internet-based services. Agomelatine is an antidepressant approved by the European Agency; it is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT_2C antagonist indicated in the treatment of major depressive episodes.

Areas covered: The present article looks at the short-term efficacy of Agomelatine assessed in two short-term placebo-controlled studies. It also looks at the long-term efficacy evaluated in one relapse prevention study.

Expert opinion: Agomelatine is an effective treatment option for both GAD and somatic anxiety. The trial, which includes an escitalopram arm, shows comparable efficacy in GAD between both antidepressants, whereas the restoration of sleep was significantly better with agomelatine. The low discontinuation rate illustrates the good tolerability and lab results show a low incidence of transient elevations in liver enzymes. Whereas uptitrated patients on a 50 mg dose have a lower chance of reaching the desired outcome than the lower 25 mg dose, those reaching this outcome have a better chance of treatment continuation.     

SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations

Post-traumatic stress disorder (PTSD) is a highly prevalent (7.8% lifetime rate) anxiety disorder with impairment in daily functioning, frequent suicidal behaviour and high rates of co-morbidity. Fortunately, PTSD is responsive to pharmacotherapy and psychotherapy. The selective serotonin reuptake inhibitors (SSRIs) are the most studied medications for PTSD, with the largest number of double-blind, placebo-controlled trials. Of the SSRIs, sertraline, paroxetine and fluoxetine have been the most extensively studied, with sertraline and paroxetine being US FDA-approved for PTSD. These studies have demonstrated that SSRIs are effective in short-term trials (6-12 weeks). Furthermore, continuation and maintenance treatment for 6-12 months decrease relapse rates. Besides being the most studied and effective drugs for PTSD, SSRIs have a favourable adverse effect profile, making them the first-line treatment for PTSD. If SSRIs are not tolerated or are ineffective, non-SSRIs should be considered. Serotonin-potentiating non-SSRIs, such as venlafaxine, nefazodone, trazodone and mirtazapine, have been evaluated in PTSD only in open-label and case studies. Because of their promising results and relatively good safety profile, they should be considered as second-line treatment. Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) have both been evaluated in a small number of double-blind, placebo-controlled studies. The results have been inconsistent but promising. In the limited comparative studies, MAOIs appeared superior to TCAs but patients continued to have residual symptoms. These drugs have significant adverse effects, such as cardiovascular complications, and safety issues, such as ease of overdose. Therefore, TCAs and MAOIs should be considered as third-line treatment. Anticonvulsants have been evaluated in PTSD in open-label studies and results have been positive for carbamazepine, valproic acid, topiramate and gabapentin. A small double-blind, placebo-controlled study demonstrated efficacy of lamotrigine for PTSD. Anticonvulsants should be considered where co-morbidity of bipolar disorder exists, and where impulsivity and anger predominate. Bupropion (amfebutamone), a predominantly noradrenergic reuptake inhibitor, was ineffective in PTSD in an open-label study. Benzodiazepines were ineffective in a double-blind, placebo-controlled study despite encouraging case reports. They should be avoided or used only short term because of potential depressogenic effects, and the possibility that they may promote or worsen PTSD. Buspirone, a non-benzodiazepine anxiolytic, was found to be effective in PTSD only in open-label studies. Recently, atypical antipsychotics were as effective as monotherapy and as an augmenter to SSRIs in open-label/case studies and small double-blind, placebo-controlled trials; atypical antipsychotics should be considered in PTSD where paranoia or flashbacks are prominent and in potentiating SSRIs in refractory cases.     

Pharmacotherapy to control behavioral symptoms in children with autism

Introduction: Autistic disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) are pervasive developmental disorders (PDDs) frequently associated with behavioral symptoms that may require pharmacotherapy to manage.

Areas covered: Behavioral symptoms in children with autism include interfering repetitive behaviors, irritability, and hyperactivity and inattention, among others. The psychotropic medications examined in this review include: serotonin reuptake inhibitors, typical and atypical antipsychotics, medications used to treat attention-deficit/hyperactivity disorder, naltrexone, buspirone, divalproex sodium, lamotrigine, levetiracetam, memantine, mirtazapine, riluzole, pioglitazone, and topiramate.

Expert opinion: For the treatment of interfering repetitive behaviors, serotonin reuptake inhibitors demonstrate less efficacy and are more poorly tolerated in children with autism compared to adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in children with autism and other PDDs. For the treatment of hyperactivity and inattention, psychostimulants demonstrate some benefit. However, they are overall less efficacious and cause more side effects in children with PDDs compared to typically developing children with attention-deficit/hyperactivity disorder. Results from double-blind, placebo-controlled trials of these agents and others for the treatment of the behavioral symptom domains described above will be discussed in this review.     

Vortioxetine: a New Treatment for Major Depressive Disorder

Introduction: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD). This medication is a serotonin reuptake inhibitor that also has a number of other potentially relevant effects on serotoninergic receptors, which may differentiate the drug’s effects from those of current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).

Areas Covered: This article will review the basic clinical pharmacology of vortioxetine, summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration (FDA), discuss relevant post-marketing studies of this drug, and offer expert commentary on the significance of this new agent in clinical practice. Pre-approval studies were identified as all randomized, placebo-controlled studies of vortioxetine listed on clinicaltrials.gov. Other referenced studies were identified via a MEDLINE database literature search in August 2015 using the key search terms, vortioxetine and Lu AA21004, combined with additional terms that included pharmacological profile, pharmacokinetics, drug interactions, adverse effects, side effects, safety, major depression, and major depressive disorder. We identified relevant systematic reviews, meta-analyses, randomized trials and preclinical studies of importance.

Expert Opinion: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. The most common side effects are nausea, vomiting and constipation. Results of several studies indicate that vortioxetine may have therapeutic effects on cognition (e.g., memory and executive functioning) that exceed that of standard antidepressants. Disadvantages include cost and the current paucity of long-term efficacy data from large clinical trials. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option.     

Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited

Introduction: Major depression is one of the most prevalent forms of mental illnesses and is among the leading causes of disability, affecting about 121 million people worldwide. Approximately 30% of patients fail to respond to present therapies. Therefore, the search for novel antidepressant drugs continues.

Areas covered: The most prescribed antidepressants are serotonin reuptake inhibitors and/or noradrenaline reuptake inhibitors, which only indirectly affect dopaminergic neurotransmission. As a consequence, residual symptoms remain, including impaired motivation and impaired pleasure. This article reviews the development of new broad-spectrum antidepressants, the triple reuptake inhibitors, which also increase brain dopamine levels.

Expert opinion: In this review, a distinction is made between the subtypes of melancholic and atypical depressions and their associated brain abnormalities and dysfunctions in neurotransmitter systems. Subsequently, we propose a hypothetical model: ‘the monoamine hypothesis revisited’ to predict what kind of pharmacological treatment will be effective in the different subtypes of depression. It is expected that the triple reuptake inhibitors, inhibiting the reuptake of all three monoamines, can produce a greater efficacy than traditional antidepressants especially in atypical depression. Since triple reuptake inhibitors may also dampen states of hyperglutamatergic activity and subsequent excitotoxicity, it is suggested that these new drugs have a considerable neuroprotective potential in major depression, especially in melancholic depression.     

Severe depression: is there a best approach?

A major depressive episode can be categorised as severe based on depressive symptoms, scores on depression rating scales, the need for hospitalisation, depressive subtypes, functional capacity, level of suicidality and the impact that the depression has on the patient. Several biological, psychological and social factors, and the presence of comorbid psychiatric or medical illnesses, impact on depression severity. A number of factors are reported to influence outcome in severe depression, including duration of illness before treatment, severity of the index episode, treatment modality used, and dosage and duration of and compliance with treatment. Potential complications of untreated severe depression include suicide, self-mutilation and refusal to eat, and treatment resistance. Several antidepressants have been studied in the treatment of severe depression. These include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline (norepinephrine) reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin 5-HT(2) receptor antagonists, monoamine oxidase inhibitors, and amfebutamone (bupropion). More recently, atypical antipsychotics have shown some utility in the management of severe and resistant depression. Data on the differential efficacy of TCAs versus SSRIs and the newer antidepressants in severe depression are mixed. Some studies have reported that TCAs are more efficacious than SSRIs; however, more recent studies have shown that TCAs and SSRIs have equivalent efficacy. There are reports that some of the newer antidepressants may be more effective than SSRIs in the treatment of severe depression, although the sample sizes in some of these studies were small. Combination therapy has been reported to be effective. The use of an SSRI-TCA combination, while somewhat controversial, may rapidly reduce depressive symptoms in some patients with severe depression. The combination of an antidepressant and an antipsychotic drug is promising and may be considered for severe depression with psychotic features. Although the role of cognitive behaviour therapy (CBT) in severe depression has not been adequately studied, a trial of CBT may be considered in severely depressed patients whose symptoms respond poorly to an adequate antidepressant trial, who are intolerant of antidepressants, have contraindications to pharmacotherapy, and who refuse medication or other somatic therapy. A combination of CBT and antidepressants may also be beneficial in some patients. Electroconvulsive therapy (ECT) may be indicated in severe psychotic depression, severe melancholic depression, resistant depression, and in patients intolerant of antidepressant medications and those with medical illnesses which contraindicate the use of antidepressants (e.g. renal, cardiac or hepatic disease).     

The role of antipsychotics in the management of fibromyalgia

Fibromyalgia is a syndrome characterized by chronic generalized pain associated with different somatic symptoms, such as sleep disturbances, fatigue, stiffness, balance problems, hypersensitivity to physical and psychological environmental stimuli, depression and anxiety. It has been estimated to affect roughly the 2-4% of the general population in most countries studied, and it has been shown to be much more prevalent in women than in men. Although its pathophysiology is not yet fully understood, it is known that both genetic and environmental factors are involved in its development. Fibromyalgia shares a high degree of co-morbidity with other conditions, including chronic headache, temporomandibular disorder, irritable bowel syndrome, major depression, anxiety disorders and chronic fatigue syndrome. Therefore, this is a syndrome difficult to treat for which multimodal treatments including physical exercise, psychological therapies and pharmacological treatment are recommended. Although different kinds of drugs have been studied for the treatment of fibromyalgia, the most widely used drugs that have the higher degree of evidence for efficacy include the α(2)δ ligands pregabalin and gabapentin, and the tricyclic antidepressants (TCAs) and serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). However, there is a need to look for newer additional therapeutic pharmacological options for the treatment of this complex and disabling disease. First- and second-generation antipsychotics have shown analgesic properties both in an experimental setting and in humans, although most of the available evidence for the treatment of human pain concerns older antipsychotics and involves clinical trials performed several decades ago. In addition, several second-generation antipsychotics, risperidone, olanzapine and quetiapine, have shown efficacy in the treatment of some anxiety disorders. Some second-generation antipsychotics, mainly quetiapine, aripiprazole and amisulpride, have demonstrated antidepressant activity, with quetiapine approved for the treatment of bipolar depression and refractory major depression, and aripiprazole approved as an adjunctive treatment for major depressive disorder. Finally, several old and new antipsychotics, including promethazine, levopromazine, olanzapine, quetiapine and ziprasidone, have been shown to improve sleep parameters in healthy subjects. Each of these properties suggests that antipsychotics could represent a new potential alternative for the treatment of fibromyalgia syndrome. To date, most of the published studies on the use of antipsychotics in the treatment of fibromyalgia syndrome have been uncontrolled, either case reports or case series, dealing with olanzapine, quetiapine, ziprasidone, levopromazine and amisulpride. The studies on olanzapine and quetiapine have suggested therapeutic efficacy although, in the case of olanzapine, hampered by tolerability problems. A double-blind controlled trial, published in 1980, showed that chlorpromazine increased slow-wave sleep and improved pain and mood disturbances. More recently, four double-blind controlled studies have explored the efficacy of quetiapine, either alone or as an add-on treatment, in fibromyalgia management. None of these trials has yet been published, although two of them have been presented as congress communications, both of them suggesting that quetiapine could be a potential alternative treatment for fibromyalgia. In summary, the current available evidence suggests that at least some antipsychotics, specifically quetiapine, could be useful for the treatment of fibromyalgia and that further studies on the efficacy of these compounds are worth pursuing.     

Pharmacological treatment for generalized anxiety disorder in adults: an update

Introduction: Modest response and remission rates for the selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, coupled with mounting evidence that the tolerability of the antidepressants (ADs) may have been overstated in the literature, has contributed to changes in prescribing patterns for generalized anxiety disorder (GAD). New interest in the absence of evidence that supports these standard therapies as superior to benzodiazepines stimulated a review of the literature.

Areas covered: A literature search was conducted in the MedLine database with search terms ‘generalized anxiety disorder’ and ‘treatment’ for purposes of including relevant literature related to pharmacologic treatment of GAD. Aside from a review of pivotal literature, the authors also included newer studies that evaluated novel drug treatments. Last, the database was searched for benzodiazepine comparisons to standard therapy secondary to concerns that such literature is sparse. The review of newer modalities and the decision to include related literature was also based on the strength of the evidence and the status of their approval for the treatment of GAD.

Expert opinion: Although ADs remain the most frequently prescribed medications for GAD, alternative and off-label therapies such as pregabalin, the atypical antipsychotics and vortioxetine are garnering interest. Based on the evidence available to us, it is our recommendation that along with the ADs, benzodiazepines be considered a possible first-line therapy in eligible patients based on the discretion and clinical judgment of the treating physician.     

Is There an Advantage to Venlafaxine in Comparison with Other Antidepressants?

The purpose of this article is to compare and contrast the benefits and limitations of antidepressant drugs. Several different classes of antidepressants are available for treatment of major depressive disorder, each with its own benefits and limitations as a result of its pharmacological profile. Tricyclic antidepressants (TCAs) and monoamine oxidase (MAO) inhibitors are effective in a large proportion of depressed patients, but their use is often limited by short- and long-term safety/tolerability problems. Selective serotonin reuptake inhibitors (SSRIs) exhibit comparable efficacy to TCAs in most patients, but may be less effective in certain patients. Additionally, SSRI use may by impacted by clinically significant drug interactions. Venlafaxine is a selective serotonin-noradrenaline reuptake inhibitor (SNRI) with unique pharmacological properties that may enhance its efficacy as well as its safety profile. In clinical trials, venlafaxine exhibits antidepressant activity in a broad range of patients with major depression, including those with melancholia, agitated or retarded symptoms, anxiety symptoms, and refractory or resistant depression. Venlafaxine has shown potential for an early onset of action and offers dose flexibility that may allow recruitment of additional responders at higher dosages. Because of its lack of affinity for muscarinic cholinergic, histaminergic, and alpha₁-adrenergic receptors, venlafaxine has a safety profile that is superior to that of TCAs. Venlafaxine also is devoid of the drug interactions characteristic of SSRIs. © 1997 John Wiley & Sons, Ltd.     

Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders

Introduction: Current drugs for the treatment of psychiatric or neurodegenerative disorders have limitations. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Drugs available for the treatment of neurodegenerative disorders are severely limited.

Areas covered: Recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating signal transduction, ER stress, cellular redox, cellular survival and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. Recent studies that suggest that reactive oxygen species might play a role as signal integrators downstream of Sig-1Rs are also covered.

Expert opinion: The advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable interventions by which stress-related cellular systems can be pharmacologically controlled.