Serotonin syndrome associated with the use of escitalopram

Escitalopram is the newest selective serotonin reuptake inhibitor (SSRI) available for use in the United States. It has been approved for the treatment of major depression and generalized anxiety disorder. It is the S-enantiomer of the SSRI citalopram and is highly serotonin specific as it has minimal effect on the reuptake of dopamine or norepinephrine. It is also a well-tolerated medication, with a side-effect profile comparable to the other SSRIs. While a number of side effects have been seen during escitalopram therapy, such as insomnia, nausea, and increased sweating, there are no reported cases of serotonin syndrome associated with escitalopram therapy to date. We present the case of a 24-year-old woman who developed serotonin syndrome after an increase in her escitalopram to 30 mg/day. We will review the diagnostic criteria of serotonin syndrome and the clinical scenarios in which serotonin syndrome can develop. We will also discuss the proposed treatments and role that polypharmacology may play in the development of this clinical entity.     

Treatment with medications affecting dopaminergic and serotonergic mechanisms: effects on fluency and anxiety in persons who stutter

Medications with dopamine antagonist properties, such as haloperidol, and those with serotonin reuptake inhibitor properties, such as clomipramine, have been shown to improve fluency. To examine the degree to which each of these two pharmacological mechanisms might independently affect fluency, a selective serotonin reuptake inhibitor, paroxetine, and a selective dopamine (D-2) antagonist, pimozide, were evaluated. Both types of medications also affect mood and anxiety, factors that could influence fluency levels. Therefore, we also evaluated the medications’ effects on generalized and speech-related anxiety and the relationships between changes in anxiety and changes in fluency in 11 subjects with a history of developmental stuttering. The randomized, double blind, placebo-controlled crossover study that was designed had to be terminated prior to completion due to severe side effects following withdrawal from paroxetine. Even with a reduced sample size (n = 6), significant improvement in percent fluent speaking time (p = 0.02) was found using a telephone task between baseline and pimozide (n = 6), with average duration of dysfluencies significantly shorter (p = 0.04) but no significant difference in the estimated number of dysfluencies per minute. This significant improvement was associated with non-significant increases in generalized anxiety, but non-significant decreases in speech-related anxiety. No significant differences were found in fluency between baseline and paroxetine (n = 5). These preliminary results suggest that fluency improvement is more likely to be mediated by dopaminergic rather than serotonergic mechanisms. Due to its side effects, however, pimozide may be considered a risk for treatment of stuttering.

Educational objectives: As a result of reading this paper the reader will describe and explain: (1) how medications may affect fluency and the rationale for selecting medications for treatment trials; (2) the interrelationship between fluency and anxiety; and (3) factors important in developing clinical trials using medications.     

SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants

The class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now comprises three medications: venlafaxine, milnacipran, and duloxetine. These drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity. Whereas milnacipran blocks 5-HT and norepinephrine reuptake with equal affinity, duloxetine has a 10-fold selectivity for 5-HT and venlafaxine a 30-fold selectivity for 5-HT. All three SNRIs are efficacious in treating a variety of anxiety disorders. There is no evidence for major differences between SNRIs and SSRIs in their efficacy in treating anxiety disorders. In contrast to SSRIs, which are generally ineffective in treating chronic pain, all three SNRIs seem to be helpful in relieving chronic pain associated with and independent of depression. Tolerability of an SNRI at therapeutic doses varies within the class. Although no direct comparative data are available, venlafaxine seems to be the least well-tolerated, combining serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with a dose-dependent cardiovascular phenomenon, principally hypertension. Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity.     

GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders

Protracted social isolation in laboratory animals causes stress, which induces a variety of behavioral abnormalities including increased aggressiveness, anxiety-related behaviors, cognitive deficits and hyper locomotion. Many of these disorders are similar to the symptoms found in psychiatric disorders, such as depression, anxiety, premenstrual dysphoria and posttraumatic stress disorders (PTSD). Recent studies have demonstrated that male mice that have been socially isolated for more than 4 weeks show: (a) reduced responsiveness of GABA(A) receptors (GABA(A)-R) to the administrations of GABA mimetic drugs at GABA(A)-R; (b) downregulated biosynthesis of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) (allopregnanolone: ALLO), a neurosteroid with a potent positive allosteric modulatory effect on the action of GABA on GABA(A)-R; and (c) alterations in the expression of GABA(A)-R subunits (i.e. a decrease of alpha1/alpha2 and gamma2 subunits and an increase of alpha4 and alpha5 subunits). The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) and its congener norfluoxetine (Nor-FLX), when administered systemically at nmol/kg doses, normalize the reduced content of brain ALLO and the reduced responsiveness of GABA(A)-R to GABA mimetic drugs (i.e. pentobarbital) and also attenuate aggressive behavior in socially isolated mice in a stereospecific manner. Although these compounds inhibit ex vivo serotonin reuptake into brain tissue, their SSRI activities require high micromol/kg dose ranges and are not stereospecific. These studies suggest that in socially isolated mice, abnormalities of GABA(A)-R signal transduction are attributable to the downregulation of ALLO production and to a switch in heteropentameric GABA(A)-R subunit assembly composition. Hence, the normalization of ALLO biosynthesis may be a new target for the development of drugs effective for psychiatric disorders related to neurosteroid biosynthesis downregulation.     

The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats

Chronic exposure to mild unpredictable stress has been found to depress the consumption of, and preference for, highly palatable sucrose solution in rats. Stress-induced behavioral deficits may be maintained for a long time, however chronic administration of clinically effective antidepressants can restore normal behavior. This is the first report showing that Sprague-Dawley rats can be used in this model. A preference deficit in this strain of rats took at least 7 weeks to develop; about twice the time required when hooded Lister or Wistar rats are used in this model. Water consumption was not effected by chronic exposure to the mild stress regime and/or by chronic administration of the selective serotonin (5-HT) releasing agent MMAI (5-methoxy-6-methyl-2-aminoindan). The stress-induced deficit in sucrose intake was completely reversed by chronic treatment with MMAI (5 mg/kg, 2 x day) over 3 weeks in the two-bottle tests. In single-bottle tests, chronic treatment with the selective 5-HT releasers, MMAI (5 mg/kg, 2 x day) or MTA (p-methylthioamphetamine; 5 mg/kg, 2 x day), reversed the deficit in rewarded behavior (anhedonia) measured as a decrease in the consumption of 1% sucrose solution in the chronic mild stress model of depression in rats. With the experimental procedure employed, and at a dose of 10 mg/kg/day of 5-HT releasers, the magnitude and onset of this effect were greater than observed following similar administration of the selective 5-HT reuptake inhibitor (SSRI) sertraline (10 mg/kg/day), used as a standard anti-depressant drug.     

Therapieresistente Depression bei älteren Patienten

Antidepressive monotherapy using selective serotonin reuptake inhibitors leads to satisfactory remission in the first 4 weeks of therapy in only 40?% of clearly depressive patients. After unsatisfactory therapy with serotonin reuptake inhibitors the change to dual antidepressants is most common. An unsatisfactory response also to this second attempt at therapy is referred to as therapy resistance. Therapy resistant depression can necessitate changing to other antidepressants, such as classical cyclic antidepressants. Therapy attempts with atypical antidepressants, such as buproprion or mirtazapin or monotherapy with a monoamine oxidase inhibitor can be carried out; however, success of therapy in severely depressive patients still remains unsatisfactory in at least 20?% of cases even after several pharmacological approaches and even after psychotherapy or augmentation strategies (e.g. lithium and antipsychotics). It is less probable that bipolar depression will respond to antidepressive therapy than recurrent unipolar depression.     

Trazodone Augmentation in OCD: A Case Series Report

Based on previous evidence that trazodone may have antiobsessional properties, the authors assessed trazodone augmentation of selective serotonin reuptake inhibitor (SSRI) therapy in five cases of obsessive-compulsive disorder. All patients showed symptomatic improvement after trazodone was added to treatment with various SSRIs, and in many cases, trazodone also improved the tolerability of SSRI therapy.     

Cognitive-behavior therapy for discontinuation of SSRI treatment of panic disorder: a case series

In this report we describe the outcome of eight outpatients with panic disorder and agoraphobia who discontinued their treatment with a selective serotonin reuptake inhibitor (SSRI) in the context of a structured, group program of cognitive-behavior therapy. All patients successfully discontinued their SSRI medication while demonstrating clinical improvement. These results were maintained at 3-month follow-up. This case series suggests that manualized CBT for discontinuation of benzodiazepine treatment for panic disorder may be successfully applied to SSRI discontinuation as well.     

First-Line Treatment for Pediatric Obsessive–Compulsive Disorder

Pediatric obsessive–compulsive disorder (OCD) is a common psychiatric disorder that impairs children’s functioning in home, school, and community settings. Once thought to be an untreatable or treatment refractory disorder, evidence-based treatments now exist for pediatric OCD. Various psychological treatment approaches for pediatric OCD have been investigated and research supports the use of cognitive-behavioral therapy (CBT) with exposure and response prevention (E/RP) and combined CBT/E/RP with serotonin reuptake inhibitor pharmacotherapy. This paper reviews these approaches and highlights the prominent role of CBT/E/RP as a first-line treatment for pediatric OCD.     

Overview of diagnosis and drug treatments of anxiety disorders

Anxiety disorders are common and often disabling. They fall into five main categories: panic disorder, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder and posttraumatic stress disorder, each of which have characteristic symptoms and cognitions. All anxiety disorders respond to drugs and psychological treatments. This review will focus on drug treatments. Recent research has emphasized the value of antidepressants especially the selective serotonin reuptake inhibitors, benzodiazepines, and related sedative-like compounds. The common co-existence of depression with all of the anxiety disorders means that the selective serotonin reuptake inhibitors are now generally considered to be the first-line treatments but the benzodiazepines have some utility especially in promoting sleep and working acutely to reduce extreme distress.     

Social isolation stress-induced aggression in mice: a model to study the pharmacology of neurosteroidogenesis

Long-term social isolation of laboratory animals is a model to study the behavioral and neurochemical consequences of the absence of social interaction in rodents. Many of the symptoms induced by isolation resemble depression and anxiety disorder symptomatology. Our studies have revealed that male mice socially isolated for more than 4 weeks, exhibit increased aggressiveness, a reduced responsiveness to GABA(A) receptor acting drugs, and a downregulation of brain levels of 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone: 3alpha,5alpha-THP), a neurosteroid endowed with potent positive allosteric modulatory activity of the action of GABA at various GABA(A) receptor subtypes. This downregulation of 3alpha,5alpha-THP appeared to be associated with the reduction of brain type I 5alpha-reductase mRNA and protein expression. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine and its metabolite norfluoxetine normalized brain 3alpha,5alpha-THP content and reduced responsiveness to GABA(A) mimetic drugs in a stereospecific manner. These drugs in nanomolar doses also reduced social isolation-induced aggressiveness with the same stereospecificity as detected in their action on 3alpha,5alpha-THP brain content, while their ex vivo inhibition of serotonin reuptake occurred at high micromolar doses and lacked stereospecificity. From these results we infer that the brain 3alpha,5alpha-THP content physiologically upregulates GABA(A) receptor responsiveness to GABA and that social isolation induces a reduction of brain 3alpha,5alpha-THP content that is probably causally related to the onset of aggression.     

Treatment-resistant panic disorder

A substantial number of patients with panic disorder and agoraphobia may remain symptomatic after standard treatment (including selective serotonin reuptake inhibitors, tricyclic antidepressants, benzodiazepines, or irreversible monamine oxidase inhibitors). In this review, recommendations for the treatment of patients with panic disorder and agoraphobia who do not respond to these drugs are provided. Nonresponse to drug treatment could be defined as a failure to achieve a 50% reduction on a standard rating scale after a minimum of 6 weeks of treatment in adequate dose. When initial treatments have failed, the medication should be changed to other standard treatments. In further attempts at treatment, drugs should be used that have shown promising results in preliminary studies, such as venlafaxine. Combination treatments may be used, such as the combination of an selective serotonin reuptake inhibitor and a benzodiazepine. Psychological treatments such as cognitive-behavioral therapy have to be considered in all patients, regardless whether they are nonresponders or not. According to existing studies, a combination of pharmacologic treatment with cognitive-behavioral therapy can be recommended.     

A pharmacological analysis of an associative learning task: 5-HT(1) to 5-HT(7) receptor subtypes function on a pavlovian/instrumental autoshaped memory

Recent studies using both invertebrates and mammals have revealed that endogenous serotonin (5-hydroxytryptamine [5-HT]) modulates plasticity processes, including learning and memory. However, little is currently known about the mechanisms, loci, or time window of the actions of 5-HT. The aim of this review is to discuss some recent results on the effects of systemic administration of selective agonists and antagonists of 5-HT on associative learning in a Pavlovian/instrumental autoshaping (P/I-A) task in rats. The results indicate that pharmacological manipulation of 5-HT1-7 receptors or 5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5-HT plays a key role in memory formation.     

Antidepressant treatment of psychotic major depression: potential role of the sigma receptor

Psychotic major depression is a severe condition that frequently proves difficult-to-treat. The most effective traditional treatments (electroconvulsive therapy and combinations of antipsychotics with tricyclic antidepressants) are associated with significant side effects, and the use of tricyclic antidepressants alone is largely ineffective. Recent evidence has indicated that the selective serotonin reuptake inhibitors, either alone or in combination with antipsychotics, may provide a desirable alternative to traditional treatments. Among selective serotonin reuptake inhibitors, fluvoxamine has been the best studied and, somewhat surprisingly, has proven effective in several studies as a monotherapy without the need to combine with an antipsychotic. It is proposed that the apparent efficacy of fluvoxamine in psychotic major depression may be related to its unique property of high affinity for the sigma 1 receptor, which is thought to play a role in psychosis and in the action of some antipsychotic drugs.     

Efficacy of noradrenergic-selective agents in the treatment of neuropsychiatric diseases

In recent years, a number of antidepressants with varying degrees of selectivity for the noradrenergic neurotransmitter system have become available. However, these agents represent a pharmacologically heterogeneous group and differ in terms of their precise side-effect profile and, possibly, their clinical efficacy. Bupropion, which is thought to act on both the dopamine and norepinephrine (NE) systems, has not been widely used as an antidepressant and has more recently been licensed as adjunctive therapy for smoking cessation. The serotonin-NE reuptake inhibitors venlafaxine and nefazodone, the noradrenergic and specific serotonergic antidepressant mirtazapine, and the selective NE reuptake inhibitor reboxetine (the only truly NE-selective agent available) have all demonstrated efficacy in the treatment of depressive disorders. Evidence is now emerging for their use in the treatment of anxiety and panic disorders. There is some suggestion of a role for noradrenergic agents in other disorders, including attention-deficit/hyperactivity disorder and social phobia. The full range of disorders for which noradrenergic agents can be used remains to be seen and further research in this area is necessary.     

Non-stimulant treatment of attention-deficit/hyperactivity disorder

Stimulants are a highly efficacious and safe treatment for attention-deficit/hyperactivity disorder (ADHD), with 75% to 90% of patients responding well if two different stimulants (amphetamine and methylphenidate) are used. Nonetheless, a subset of ADHD patients will either fail to respond to stimulants or have side effects that preclude their use (tics, severe loss of appetite, marked insomnia). For such patients, there are a number of non-stimulant agents that serve as second-line treatments. Tricyclic antidepressants (TCAs) are the most studied of these drugs. They are superior to placebo in the treatment of ADHD and may reduce abnormal movements in patients with ADHD/tic disorder. TCAs often produce side effects of sedation, dry mouth, and constipation. Bupropion is superior to placebo in the treatment of ADHD and has a more favorable side-effect profile than the TCAs. A new selective norepinephrine reuptake inhibitor, atomoxetine, has been shown to be efficacious in the treatment of ADHD and has recently received an approvable letter from the Food and Drug Administration. The a-agonists clonidine and guanfacine have also been used as alternative agents in ADHD, though the controlled data are more limited. A recent controlled clinical trial suggests a combination of methylphenidate and clonidine has advantages in the treatment of comorbid ADHD and tics over either medication alone. Clinical guidelines for each of these agents, as well as their use in combination with stimulants in comorbid conditions, will be discussed.     

Psychotherapy and (or) Medications for Depression in Youth? An Evidence-Based Review with Recommendations for Treatment

This article reviews existing research pertaining to antidepressant medications, psychotherapy, and their combined efficacy in the treatment of clinical depression in youth. Based on this review, we recommend that youth depression and its treatment can be readily understood from a social-psycho-bio model. We maintain that this model presents an alternative conceptualization to the dominant biopsychosocial model, which implies the primacy of biological contributors. Further, our review indicates that psychotherapy should be the frontline treatment for youth with depression and that little scientific evidence suggests that combined psychotherapy and medication treatment is more effective than psychotherapy alone. Due primarily to safety issues, selective serotonin reuptake inhibitors should be initiated only in conjunction with psychotherapy and/or supportive monitoring.     

Extinction-induced "despair" in the water maze, exploratory behavior and fear: effects of chronic antidepressant treatment

In former studies, we found evidence for the hypothesis that withdrawal of negative reinforcement presents a major source for stress and despair. Specifically, the removal of a hidden platform in the water maze induced extinction of previously reinforced escape behavior and behavioral immobility, indicative of "despair", which also correlated with indices of fear. Here, we tested the effects of antidepressants on extinction in the water maze, and expected that such drugs would attenuate the rate of extinction of a conditioned place preference (CPP) and also any emotionally relevant behavior that is induced by the loss of reinforcement, such as immobility. Adult male Wistar rats were trained to escape onto a hidden platform for 10 days. Daily treatment with desipramine hydrochloride (DMI, 10mg/kg) or fluoxetine (FLX, 10 mg/kg) commenced 1 day before the first of 11 extinction trials without the platform, administered 48 h apart, and continued thereafter, as the rats were tested in an open field and elevated-plus maze. As compared to controls, DMI increased the resistance-to-extinction of CPP, attenuated immobility, and increased wall climbing behavior. In the open field, DMI reduced activity levels, but was without effect on traditional fear parameters in the elevated-plus maze. FLX, by contrast, increased immobility during the extinction trials and fear in the elevated-plus maze. The withdrawal of reinforcement induced "despair" that was alleviated by the noradrenaline reuptake inhibitor DMI. The effects of the selective serotonin reuptake inhibitor FLX on immobility and fear may be explained in terms of its side effect profile.     

Evidence for the involvement of brain GABA and serotonin systems in the anticonflict effects of chlordiazepoxide in rats

Using male hooded Lister rats the effects of GABAergic and serotonergic treatments alone and with chlordiazepoxide (CDP) were compared with the behavioral effects of CDP in a conditioned conflict procedure with three components; Reward, Time Out, and Conflict. CDP (2.5, 5.0, and 10.0 mg/kg ip) dose- relatedly increased punished and time out responding, but increased rewarded responding in an inversely dose-related manner. Punished responding was enhanced by chronic treatment to a rate which remained stable between 9 and 19 injections. The GABA transaminase inhibitor ethanolamine-O-sulfate (EOS), given chronically in drinking water (5.0 mg/ml), increased punished responding linearly to a high stable level after 2-3 weeks. Rewarded and time out responding were less substantially increased. CDP given with EOS dose- relatedly increased time out and punished responding substantially above the rates found with either treatment alone. The GABA antagonist picrotoxin blocked the increase in punished and time out responding found with EOS and CDP alone. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA; 100 mg/kg x 3) linearly increased punished responding for the first week of treatment. CDP with PCPA selectively and significantly increased punished responding above the rates for either treatment alone, but the increases were not as substantial as those with EOS + CDP. The serotonin reuptake inhibitor Wy 25093 reduced increases in time out and punished responding under CDP, and the precursor 5-hydroxytryptophan (5-HTP) counteracted increases in punished responding under PCPA but also substantially reduced rewarded responding. These results provide evidence that both increased GABA and decreased serotonin transmission are involved in the anticonflict effects of CDP, as EOS and PCPA both mimicked and potentiated effects of CDP, while picrotoxin, Wy 25093, and 5-HTP counteracted them.(ABSTRACT TRUNCATED AT 250 WORDS)     

A New Unified Treatment Approach for Emotional Disorders Based on Emotion Science

ABSTRACT— Research on the nature of emotional disorders points toward a common set of diatheses (underlying psychological vulnerabilities) and functionally (but not superficially) similar expression of pathological emotional responding (e.g., Barlow, 2002 ). Successful drug treatments for different emotional disorders are very similar, with selective serotonin reuptake inhibitors or related compounds in wide use. Successful psychological treatments, on the other hand, are currently specifically targeted to each individual disorder. Distilling common principles among existing empirically supported psychological treatments, and giving attention to new findings on emotion regulation and dysregulation from emotion science, we propose and describe a new unified psychological treatment for emotional disorders.