Depression and pain: An appraisal of cost effectiveness and cost utility of antidepressants

BackgroundAlthough depression and chronic pain frequently co-occur, there is a lack of clarity in the literature regarding the cost-effectiveness and cost-utility of antidepressants in the presence of these two conditions. From the perspective of healthcare provider, the current study aims to compare the cost-effectiveness and cost-utility of antidepressants in a national cohort of depressed patients with and without comorbid pain conditions.MethodsAdult patients prescribed with antidepressants for depression were identified from the National Health Insurance Research Database in Taiwan (n = 96,501). By using remission as effectiveness measure and quality-adjusted life years (QALYs) as utility measure, the cost-effectiveness and cost-utility were compared across selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), as well as by the presence of comorbid painful physical symptoms (PPS).ResultsSSRIs dominated SNRIs in both the cost-effectiveness and cost-utility regardless of comorbid PPS. In comparison with TCAs, SSRIs were likely to be the cost-effective option for patients without PPS. In patients with PPS, the cost-utility advantage for SSRIs over TCAs varied with threshold willingness-to-pay levels. Comorbid PPS may be considered an effect modifier of the cost-utility comparisons between SSRIs and TCAs.ConclusionsFor depressed patients without PPS, SSRIs are likely to be cost-effective in improving remission rates and QALYs compared to TCAs and SNRIs. However, to improve cost-utility in those with comorbid PPS, people need to choose between SSRIs and TCAs according to threshold willingness-to-pay levels. Future research is warranted to clarify the impacts of different pain conditions on the economic evaluations of pharmacological treatments in patients with depression.     

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.     

Translating the evidence on atypical depression into clinical practice

Subtypes of depression need to be recognized and diagnosed in order to properly treat patients who have depression but present with different symptoms from one another. Different pharmacotherapuetic strategies may work better for different subtypes. Selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) have been studied for the treatment of atypical depression. To date, MAOIs have been shown to be the most efficacious agents in treating atypical depression; however, many MAOIs nonselectively and irreversibly inhibit both MAO substrates, require tyramine-restricted diets, and may produce weight gain, cardiovascular side effects, or sexual dysfunction. A newer MAOI, the transdermal formulation of selegiline, may provide all of the efficacy of the older MAOIs in treating atypical depression without causing as great of adverse events and no diet restrictions.     

SSRIs and SNRIs: broad spectrum of efficacy beyond major depression

Originally studied and introduced for the treatment of depression, the selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) have proven effective for a broad range of psychiatric illnesses, including several anxiety disorders, bulimia, and dysthymia. These drugs have in common important effects on the serotonergic (5-HT) neurotransmission system, which is involved in mediating a substantial number of important functions, including mood, aggression, sexual behavior, and pain. In addition, some of the new antidepressants, like venlafaxine/venlafaxine XR, also have effects on the noradrenergic neurotransmission system, which also appears important in mood and anxiety disorders. These new drugs, because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse side effects of tricyclic antidepressants and monoamine oxidase inhibitors. Consequently, in addition to being the usual first-line treatments for major depression, they are also first-line for panic disorder, obsessive-compulsive disorder, social phobia, posttraumatic stress disorder, and bulimia. They may also be the best medication treatments for dysthymia and generalized anxiety disorder. Further advances in psychopharmacology will be driven by discoveries from brain imaging and molecular biological research.     

Psychopharmacotherapy of somatic symptoms disorders

Abstract

Somatic symptoms are often common causes for medical consultation. The treatment of somatic symptoms disorders is complicated by lack of boundary, conceptual clarity, and overemphasis on psychosocial causation and effectiveness of psychological treatments. In clinical practice all classes of psychotropics are used to treat somatic symptoms disorder. Five principal groups of drugs such as tricyclic antidepressants (TCA), serotonin reuptake inhibitors (SSRI), serotonin and noradrenalin reuptake inhibitors (SNRI), atypical antipsychotics and herbal medication are systematically studied. The evidence indicates that all five groups are effective in a wide range of disorders. All classes of antidepressants seem to be effective against somatoform and related disorders. SSRIs are more effective against hypochondriasis and body dysmorphic disorder (BDD), and SNRIs appear to be more effective than other antidepressants when pain is the predominant symptom. Research leaves many unanswered questions regarding dosing, duration of treatment, sustainability of improvement in the long term and differential response to different class drugs. Further studies need to focus on treatments based on clinical features/psychopathology and collaborative research with other specialists in understanding the relation of somatic symptom disorders and functional somatic syndromes (FSS), and comparing psychotropics and non-psychotropics and combinations treatments.     

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 effectiveness of antidepressants in the treatment of chronic non-cancer pain--a review

Antidepressants are often applied in the treatment of chronic pain. Analgesic action of tricyclic antidepressants (TCAs) has been extensively studied and proven. TCAs are associated with a number of adverse effects which are inconvenient for patients. The newer antidepressants have fewer side effects and equivalent efficacy on mood disorders. This article reviews the available publications (mainly placebo-controlled trials) concerning the efficacy of these medications in the treatment of chronic pain. The data regarding selective serotonin reuptake inhibitors (SSRI) are conflicting. Trazodone (a serotonin-reuptake inhibitor as well as a postsynaptic serotonin receptor antagonist) does not appear to be effective for the treatment of chronic pain. No placebo-controlled studies are available for noradrenergic and specific serotoninergic antidepressant (NaSSA)--mirtazapine and noradrenaline reuptake inhibitor (NaRI)--reboxetine. Bupropion, a noradrenaline and dopamine-reuptake inhibitor appears to be effective in the treatment of neuropathic pain. Venlafaxine--selective serotonin and noradrenergic reuptake inhibitors (SNRI) was shown to be effective in the treatment of different kinds of pain. Duloxetine (SNRI) is effective in relieving both the emotional and painful physical symptoms of depression. Additional randomized, controlled trials are necessary to fully evaluate the role of new antidepressants in the treatment of chronic pain.     

Douleur morale,douleur physique : mécanismes neurobiologiques et traitement

Emotional pain endured by depressed patients often resembles to physical pain. Overlaps between pain and suffering are based on several observations and suggest common pathophysiological mechanisms: Neuroimaging studies have highlighted neural networks common to emotional pain and physical pain in healthy subjects; major depressive disorders often occur in patients with chronic pain, and conversely, painful events often occur in depressed patients; antidepressants, including tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors (SNRIs), are efficient in the treatment of chronic pain, and conversely, certain analgesics are useful in relieving grief. Better understanding of the pathophysiology of emotional pain and its relationship with physical pain could lead to other therapeutic approaches, some of which, such as ketamine, are promising.     

Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature.

OBJECTIVE: To review the literature for reported cases of mania related to discontinuing antidepressant treatment, as well as for possible explanations of this phenomenon, and to present a case report. METHOD: We undertook a literature review through the PubMed index, using the key words mania, antidepressant withdrawal, and antidepressants in bipolar disorder. We reviewed 11 articles featuring 23 cases. Where available, we noted and tabulated certain parameters for both bipolar disorder (BD) and unipolar depression. We use a case example to illustrate the phenomenon of mania induced by antidepressant withdrawal. RESULTS: For patients with unipolar depression, we found 17 reported cases of mania induced by antidepressant withdrawal. Antidepressants implicated included tricyclic antidepressants (TCAs) (12/17), monoamine oxidase inhibitors (MAOIs) (2/17), trazodone (1/17), mirtazapine (1/17), and paroxetine (1/17). For patients with BD, we found 19 reported cases of mania induced by antidepressant withdrawal, including our own case example. Of these, selective serotonin reuptake inhibitors (SSRIs) (10/19), TCAs (4/19), MAOIs (2/19), and serotonin norepinephrine reuptake inhibitors (SNRIs) (2/19) were implicated. CONCLUSION: Our case report supports the observation of antidepressant withdrawal-induced mania in patients with BD. It is distinguishable from antidepressant-induced mania, physiological drug withdrawal, and mania as a natural course of the illness. Many theories have been put forward to explain this occurrence. Noradrenergic hyperactivity and "withdrawal-induced cholinergic overdrive and the cholinergic-monoaminergic system" are the 2 most investigated and supported models. The former is limited by poor clinical correlation and the latter by its applicability only to anticholinergic drugs.     

Psychopharmacology of anxiety disorders

Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.     

Fluoxetine: an update of its use in major depressive disorder in adults

The selective serotonin reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychiatry. They have emphasized the pathophysiological role of serotonin (5-HT) in affective disorders. Indeed, SSRIs were developed for inhibition of the neuronal uptake for serotonin (5-HT), a property shared with the TCAs (tricyclic anti-depressants), but without affecting the other various central neuroreceptors (ie, histamine, acetylcholine and adrenergic receptors) that are responsible for many of the safety and tolerability problems with TCAs. In this way, fluoxetine and other SSRIs represent a major advance over tricyclics, because of their lower toxicity. While the position of fluoxetine relative to other selective serotoninergic antidepressants requires further investigation, fluoxetine has a more favorable tolerability profile for a similar efficacy in comparison to tricyclic antidepressants. The pharmacokinetic and pharmacodynamic properties of fluoxetine are well described. After oral administration, fluoxetine is almost completely absorbed. Due to hepatic first-pass metabolism, the oral bioavailability is < 90%. Fluoxetine has a half-life of 2-7 days, whereas the half-life of norfluoxetine ranges between 4 and 15 days. This long half-life of fluoxetine may be advantageous when the patient omits a dose since drug concentrations decrease slightly. On the other hand, in the case of fluoxetine non-response, long washout periods are necessary before switching the patient to a TCA or a MAO inhibitor to avoid drug interactions or the development of a 5-HT syndrome. As a class, SSRIs are considerably more selective in comparison to TCAs in terms of their central nervous system mechanisms, but differ in other clinically relevant aspects. This action affects several specific 5-HT receptors, which, in turn, effects a multitude of neural systems and signalization pathways. However, despite the facilitating serotoninergic neurotransmission, the direct mechanism by which a SSRI exerts its anti-depressant activity remains uncertain. The therapeutic response in major depression for SSRIs (ie 15-20 days) maybe due to a progressive desensitization of somatodendritic 5-HT autoreceptors in the midbrain raphe nucleus. On the other hand, it has also been postulated that 5-HT is a modulator of several neurophysiological pathways, including dopamine, noradrenaline, but also neurotrophic factors, intra-cytoplasmic phosphorylations and nuclear genes expression. Therapeutic activity of SSRIs may finally results in a complex modulation and homeostasis between monoaminergic neurotransmisson and neuronal plasticity. In term of health-care, the introduction of fluoxetine and other SSRIs in the 1980s has radically changed the treatment of depressive disorder worldwide and they have emerged as the first line of treatment for depressive disorders. The efficacy of fluoxetine is now well established in the treatment of major depressive disorder. Indeed, this efficacy has been assessed in numerous clinical controlled trials involving patients with major depressive disorders. Meta-analysis were carried out and confirmed that fluoxetine was as effective as the tricyclic antidepressants, and appeared more effective than placebo in improving the symptoms of depression. However, there is no scientific evidence to suggest that any one SSRI is more effective than another, but not all patients respond to the same agent. Looking to the future, we need further comparative studies of the SSRIs with the next generation of antidepressants such as 5-HT noradrenaline reuptake inhibitors (SNRIs, Venlafaxine). Actually, it is interesting to note that, whereas the emphasis with the SSRIs has been on their selectivity, recent developments have tended to move towards less selective agents, and now to other neurobiological pathways (ie neurotrophic factors). Finally, fluoxetine, in common with other SSRIs, remains today a first-line treatment option for major depressive disorder.     

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.     

Mechanism of action of antidepressant medications

The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.     

Use of Antidepressants in Treatment of Comorbid Diabetes Mellitus and Depression as Well as in Diabetic Neuropathy

After a brief review of epidemiology, the focus is on biochemistry of diabetes. Animal and human studies are reviewed in terms of the impact of alterations in catecholamines and serotonin (5-hydroxytryptamine, 5HT) on glucose utilization. Then, the implications of these experimental results for the choice of antidepressant in comorbid diabetes mellitus and depression as well as in diabetic neuropathy are discussed. Results of clinical investigations are then reviewed in terms of the above hypotheses. An Index Medicus Search for the past 10 years was supplemented by references from previous related reviews of the topic as well as by pending results, where available, not previously published. The range of prevalence of depression in diabetic patients has been 8–27%, depending on study criteria and procedures. An increase of catecholamines appears to increase glucose while both reducing insulin release and reducing sensitivity to insulin that is available. In contrast, increases in serotonergic function by increased precursor, increased release, or blocked metabolism and blocked reuptake in contrast seem to increase sensitivity to insulin and reduce plasma glucose. There have been six studies of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), at a dose of 60 mg/day pursued up to 12 months that have demonstrated that medication's usefulness in diabetic patients, with reductions in weight (to 9.3 kg), in FPG (to 45 mg%), and in HbA1c (to 2.5%). In studies in comorbid diabetes mellitus and depression, nortriptyline, a norepinephrine reuptake inhibitor that produces increased synaptic catechols, has led to worsening of indices of glucose control. However, fluoxetine and sertraline, both selective serotonin reuptake inhibitors, in the same patient group, have produced results consistent with reductions in glucose levels. In diabetic neuropathy, perhaps due to the fact that catecholamines and serotonin may both be implicated in pain pathways, dual-action antidepressants appear more effective at lower doses than do specific serotonergic agents. The tricyclic antidepressants (TCA) (66.7%) have had success in double-blind studies, particularly imipramine, with a 81% response rate. Yet, there are positive reports concerning the SSRIs (paroxetine, citalopram, sertraline), as well as nefazodone, that focus on serotonin selectivity. Conclusions: In comorbid diabetes mellitus and depression, most evidence supports the use of fluoxetine in control of glucose handling. Other characteristics in terms dosing, drug interactions, cognition, and sleep make sertraline an attractive alternative agent. In diabetic neuropathy without depression, the best choices among non-TCAs may include sertraline, citalopram, and perhaps, venlafaxine, since the TCAs appear to increase cravings and increase FBG levels.     

Enhancing central noradrenergic function in depression: is there still a place for a new antidepressant?

Noradrenaline has long played a key role in the way the etiology of depression is conceptualized and in the mechanism of action of many current antidepressants. Tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), selective noradrenaline reuptake inhibitors (NRIs), the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine, and many atypicals, like mianserin and bupropion, influence, at least in part, central noradrenergic function. Enhancement of noradrenergic function may be particularly helpful in patients with melancholia. However, while noradrenaline will continue to be a target for research into the etiology and treatment of depression, it is unlikely that antidepressants acting solely on noradrenaline will be pursued.     

Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: A critical review

OBJECTIVE: To critically review the antiobsessional properties of serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine and clomipramine) in the treatment of obsessive-compulsive disorder (OCD) as an alternative to selective serotonin reuptake inhibitors (SSRIs), which are currently considered the first-line treatment of OCD. DATA SOURCES: A MEDLINE search was performed to identify clinical trials with the SNRIs venlafaxine and clomipramine published from 1996 to 2004 (keywords: SNRIs, venlafaxine, duloxetine, and clomipramine, each matched individually with the term OCD), focusing on the best-designed studies for inclusion. DATA SYNTHESIS: Much of the literature about SNRIs in OCD supports the efficacy of these compounds in the treatment of OCD. However, double-blind, placebo-controlled studies with venlafaxine are lacking, and the most relevant studies consist of active comparison trials between SNRIs and SSRIs. In these studies, SNRIs seem to be as effective as SSRIs in OCD; SNRIs might be preferred for patients with certain types of treatment-resistant OCD or those with particular comorbid conditions. A large number of placebo-controlled and active comparison trials with clomipramine document efficacy in OCD, and meta-analytic studies suggest a small superiority over SSRIs. Compared with clomipramine, the SNRI venlafaxine showed fewer side effects and better tolerability. CONCLUSION: The SNRIs may represent a valid alternative to the SSRIs, particularly in specific cases. Double-blind, placebo-controlled studies are, however, needed to confirm the positive findings reported by several studies with venlafaxine.     

Treatment of depression in patients with heart disease.

There is a growing body of evidence that depression significantly and adversely affects cardiovascular health. Perhaps the most prominent finding is the documented increase in mortality rate in patients with depression after myocardial infarction. The critical questions of interest to both the clinician and researcher are whether there are safe and effective treatments for depression in patients with heart disease and whether treatment of depression reduces the increased risk of cardiac morbidity and mortality. Though the data are limited and are primarily from open or comparator trials, the tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and specific psychotherapies appear to be effective for treatment of depression in patients with ischemic heart disease (IHD), and response rates are comparable to those reported in depressed patients without heart disease; however, there has been only one placebo-controlled trial to date, and therefore it is premature to come to definitive conclusions regarding the efficacy of antidepressant therapies in this patient population. With respect to safety, the TCAs are associated with documented adverse cardiovascular effects, including increases in heart rate, orthostatic hypotension, and conduction delays. Use of TCAs in patients with IHD carries a proven increased risk of cardiac morbidity and perhaps of mortality as well. The SSRIs appear to be relatively safe and effective treatment for depression in patients with comorbid IHD.