Mixed Serotonin Research Articles

Risperidone Associated With Acute Pulmonary Thromboembolism: A Case Report

Antipsychotic drugs (APs) are widely used drugs for schizophrenia. For decades, these agents are frequently associated with some side-effects, including increased the risk of Venous Thromboembolism (VTE). A case of a man (53 years old) with schizophrenia was reported in this study. The man with no identified risk factor for thromboembolism, and developed Pulmonary Embolism (PE) and Deep Vein Thrombosis (DVT) after treatment with risperidone 2 years. The current case indicates that use of risperidone for long time can be associated with the risk of PTE and DVT. Risperidone is a Second-Generation Antipsychotic medication (SGA), as a mixed serotonin 5HT2 and dopamine D2 receptor antagonist possibly implicated in this adverse event. As suggested by this observation, VTE and PTE risk not just appears to new users, so they should be vigilant monitored to ensure early detection and prompt treatment of VET and PTE during medication.

Are Antidepressants Mood Agents Or Anxiolytic Drugs?

Many advances have been made in the treatment of depression with the recent discovery of selective serotonin reuptake inhibitors (SSRIs) and mixed serotonin and norepinephrine reuptake inhibitors (SNRIs).

Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation

Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming. This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects. Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7h after drug administration during three drug conditions: placebo, LSD (100mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire. LSD, compared with placebo, significantly increased cognitive bizarreness (p<0.001). The LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control (p<0.05). Both LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin. LSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.

The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation

A core aspect of the human self is the attribution ofpersonal relevance to everyday stimuli enabling us to experience our environment as meaningful [1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders[2, 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point tothe crucial role of the 5-HT2AR subtype andcortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution.

Abstract PR314

Background & Objectives: Chronic non-malignant neuropathic pain management is a major challenge for the clinicians despite a wide range of analgesics and pain treatment protocols. First, second, and third line drug treatments for neuropathic pain include the use of anticonvulsants, tricyclic antidepressants, mixed serotonin and norepinephrine reuptake inhibitors, opioids and other various treatment opportunities. However, the results of these treatment protocols for neuropathic pain management are heterogeneous and sometimes with short term outcomes. Although nerve blocks have been recognized as a major modality in chronic pain management, they are not included in guidelines for chronic non-malignant neuropathic pain management. The aim of our study was to investigate whether administration of peripheral nerve blocks with local anesthetic and corticosteroid significantly reduced pain in patients with chronic non-malignant neuropathic pain resistant to standard treatment, based on guidelines for chronic neuropathic pain management. Materials & Methods: 55 patients with chronic non-malignant neuropathic pain that was resistant to standard treatment based on guidelines for neuropathic pain were included in our study. The mixture of local anesthetic (0.125% levobupivacaine) and corticosteroid (betamethasone) was used to perform the blocks of peripheral nerves. Pain was assessed by the use of numeric pain rating scale (NPRS), with range 0-10 (0-no pain to 10-worst possible pain). Pain was evaluated before the application of peripheral nerve blocks and 3 weeks after. Differences between groups of patients were assessed by Wilcoxon signed rank test. All P-values were two-sided and statistical significance (p) was set at a value of 0.01. Results: A Wilcoxon signed rank test revealed a statistically significant reduction in pain, assessed on NPRS, following administration of peripheral nerve blocks, z= –6.47, p< 0.01, with a large effect size (r= 0.62). The median score on NPRS decreased from pre-peripheral nerve block administration (Median= 9; interquartile range (8-10)) to post-peripheral nerve block administration (Median= 3; interquartile range (2-5)). Conclusion: Our results suggest that peripheral nerve blocks improve pain management in patients with chronic non-malignant neuropathic pain and that these interventions could be used as therapeutic approach for patients with neuropathic pain resistant to other treatment alternatives.

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases.

The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity.

Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

Prise en charge de la douleur neuropathique

Neuropathic pain is often underestimated and not adequately treated. The DN4 scale is very useful for its identification since it will benefit from pharmacological and non-pharmacological specific alternative care. The pathophysiological mechanisms involve the hyperexcitability of nociceptive pathways or decreased inhibitory descending controls that will be the target of pharmacological treatments. Frontline molecules are antidepressants (tricyclics and mixed serotonin and norepinephrine reuptake inhibitors) and antiepileptics (α2δ calcium channel inhibitors). However, these drugs will only have a partial efficacy on pain. The therapeutic strategy is based on reasonable goals, starting with a monotherapy adapted to the patient's symptoms and comorbidities and increased step by step. Patient compliance to contract is essential and requires clear and complete information. The impact on profession, social and family integration should rapidly be taken into account. In case of inefficiency, a change of the first-line treatment or an association could be considered. Some indications justify a specific therapy. Patients with resistant chronic pain should be sent to a specialized centre. New drugs are being studied and non-pharmacological support must be evaluated.

The safety and efficacy of vortioxetine for acute treatment of major depressive disorder: a systematic review and meta-analysis.

BackgroundVortioxetine is the first mixed serotonin agonist and antagonist antidepressant approved in the US. We sought to evaluate all published and unpublished data available to determine the efficacy and harms of vortioxetine in adults with major depressive disorder.MethodsWe used a predefined search strategy of MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Drugs@FDA to identify studies evaluating vortioxetine in the acute treatment of major depressive disorder. Only randomized controlled trials (RCTs) that provided results on relevant clinical efficacy and safety outcomes were included. Study quality was assessed and results were pooled using mixed effect meta-analyses where applicable.ResultsWe identified 11 RCTs with 6,145 participants meeting inclusion criteria (eight were published and three were unpublished). The trials did not exceed 8 weeks in duration. The response rate with vortioxetine was significantly higher for 1-mg (relative risk (RR) = 1.91; 95% confidence interval (CI) 1.36 to 2.69), 5-mg (RR = 1.33; 95% CI 1.10 to 1.61), 10-mg (RR = 1.42; 95% CI 1.21 to 1.67), and 20-mg doses (RR = 1.58; 95% CI 1.19 to 2.08) compared to placebo. Remission rates were significantly higher for the 10-mg group (RR = 1.45; 95% CI 1.18 to 1.77) and the 20-mg group (RR = 1.68; 95% CI 1.19 to 2.37) compared to placebo. Meta-regression of dose on the log odds ratio of response was not statistically significant (β = 0.01; P = 0.46). Vortioxetine response rates were lower than active serotonin and norepinephrine reuptake inhibitor (SNRI) comparators for the 5-mg (RR = 0.88; 95% CI 0.80 to 0.98), 15-mg (RR = 0.78; 95% CI 0.68 to 0.90), and 20-mg (RR = 0.82; 95% CI 0.72 to 0.94) doses. The most common adverse events were nausea and vomiting which increased in frequency with higher doses.ConclusionsVortioxetine was significantly more effective than placebo for acute treatment of major depressive disorder (MDD). Although treatment effect estimates varied substantially between studies, a dose effect was not observed. Vortioxetine does not appear to be more effective, and is potentially less effective, than an SNRI.Systematic review registrationPROSPERO CRD42013006198.Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-015-0001-y) contains supplementary material, which is available to authorized users.

Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder.

Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic- and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.

The Pharmacokinetic and Safety Profiles of Blonanserin in Healthy Chinese Volunteers After Single Fasting Doses and Single and Multiple Postprandial Doses

Blonanserin is a novel atypical antipsychotic drug acting as a mixed serotonin 5-HT2A and dopamine D2 receptor antagonist. This study investigated the pharmacokinetics and safety of blonanserin in healthy Chinese males. This was an open-label trial with two parts. Twenty-four subjects were enrolled in part A to receive a single fasting dose of 4 or 8 mg blonanserin (each n = 12); part B recruited 12 subjects and administered single and sequentially twice-daily multiple postprandial doses of blonanserin 2 mg for 9 days. Serial blood samples were taken for the bioassay of plasma blonanserin and its four metabolites during both sub-studies. Safety was assessed, including repeat measurements of fasting serum prolactin, insulin, triglyceride and cholesterol. Blonanserin was rapidly absorbed, accompanied with immediate plasma concentration elevation of the N-oxide form (M2) and gradual rises of the N-deethylated form (M1) and its downstream metabolites. The mean elimination half-life of blonanserin (7.7-11.9 h) was much longer than that of M2 (1.2-1.3 h) but shorter than that of M1 (26.4-31.4 h) after single fasting doses. After food intake, a single dose of 2 mg blonanserin resulted in total exposure and peak concentrations of blonanserin similar to those observed with a single fasting dose of blonanserin 4 mg. Moreover, the relationship of metabolite over parent compound ratio was different between M1 and M2 after single and multiple postprandial administrations (single dose vs multiple dose: M1, 0.33 vs 0.75; M2, 0.13 vs 0.067). Mild but transient increases of prolactin, insulin and triglyceride were observed. The pharmacokinetics of blonanserin in Chinese subjects were similar to those observed in Japanese subjects. This study suggested that food intake not only increases the bioavailability of blonanserin but differently affects the pharmacokinetics of its metabolites as well. The drug was safe and well tolerated in healthy Chinese males.

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

Some users of 3,4-methylenedioxymethylamphetamine (MDMA or ecstasy) abuse this drug and/or become concerned about their use. These individuals would benefit greatly from the development of pharmacological strategies to reduce MDMA consumption. We have previously observed that antipsychotics block acquisition and expression of the conditioned place preference (CPP) induced by MDMA, though they do not modify priming-induced reinstatement of MDMA-induced CPP after extinction. In the present study we have evaluated the capacity of the mixed serotonin (5-HT2A)/dopamine (DA D2) antagonist risperidone to block acquisition and reinstatement of MDMA induced-CPP. Adolescent male mice conditioned with 10mg/kg of MDMA were treated with 0.1 or 0.3mg/kg of risperidone during acquisition of conditioning (experiment 1) or before the reinstatement test (experiment 2). Risperidone was devoid of motivational effects in the CPP paradigm, but the higher dose blocked acquisition of the MDMA-induced CPP. This behavioural effect was accompanied by an increase in the level of dopamine transporters in the striatum. However, risperidone had no effects on reinstatement of the CPP induced by a priming of MDMA. Our results suggest that risperidone induces the same effects as other antipsychotics, in which case its efficacy for treating MDMA abuse is limited.

From Bench to Bedside: Understanding the Science behind the Pharmacologic Management of MDMA- and other Sympathomimetic-Mediated Hyperthermia

Objective: To evaluate the scientific rationale and efficacy of pharmacologic and nonpharmacologic treatments for sympathomimetic-induced hyperthermia and related sequelae. Data Sources: Literature was accessed through MEDLINE (1940-September 2010) using the terms MDMA [3,4-methylenedioxymethamphetamine], methamphetamine, toxicity, and hyperthermia. In addition, reference citations from identified publications were reviewed. Study Selection and Data Extraction: All articles written in English identified from data sources were evaluated. Data Synthesis: The treatment of sympathomimetic-induced hyperthermia is a challenging problem for health-care professionals. The lack of clinical trials further complicates the development of evidence-based treatment algorithms. Preclinical studies have mostly been with the sympathomimetic MDMA and have demonstrated a reversal of MDMA-induced hyperthermia with a mixed serotonin 5-HT1A agonist/5-HT2A antagonist or mixed α1- and β1,2,3-adrenergic receptor antagonists. Conclusions: Because of the nature by which patients are exposed to these agents, therapeutic interventions for sympathomimetic-mediated hyperthermia still lack evidence from clinical trials with human subjects. Pharmacologic treatments that should be avoided are antipyretics and the ryanodine receptor antagonist dantrolene. Promising future therapies may involve mixed 5-HT1A agonist/5-HT2A antagonists such as the atypical antipsychotic olanzapine, or mixed α1- and β1,2,3-adrenergic receptor antagonists such as carvedilol, as current preclinical research suggests.

Iloperidone for the Management of Adults with Schizophrenia

Background Iloperidone is a second-generation antipsychotic drug approved in May 2009 by the US Food and Drug Administration (FDA) for the acute treatment of schizophrenia in adults. It is a piperidinyl-benzisoxazole derivative with mixed serotonin (5HT2A) and D2 dopamine antagonist properties. Objective The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, safety, and role in treatment for iloperidone in schizophrenia. Methods Scientific and clinical data were collected through searches of PubMed, ClinicalTrials.gov, International Pharmaceutical Abstracts, and the FDA, using the search term iloperidone, and limited to English-language articles. Reference lists were reviewed for additional publications. Dates included the beginning of the database through 2010. No limits were placed on study design. Results In a 4-week Phase III trial, iloperidone 12 mg twice daily lowered the Positive and Negative Syndrome Scale (PANSS) total scores to a significantly greater extent than did placebo (−12 vs −7.1; P < 0.01). The ziprasidone active control also separated from placebo (−12.3 vs −7.1; P < 0.05). A pooled analysis of 3 Phase III trials compared iloperidone in divided doses to placebo. The primary outcome was reduction in PANSS scores. Study 1 included iloperidone 4, 8, or 12 mg/d, haloperidol as an active control, and placebo. The PANSS reduction in the 12 mg/d group was significantly greater at end point versus baseline when compared with placebo (−9.9 vs −4.6; P = 0.047). Study 2 included iloperidone 4 to 8 mg/d or 10 to 16 mg/d, risperidone 4 to 8 mg/d, or placebo. The primary efficacy measure was change from baseline to end point in the Brief Psychiatric Rating Scale (BPRS). Improvement from baseline on all iloperidone doses was significantly greater than with placebo (4–8 mg/d group: −6.2, P = 0.012; 10–16 mg/d group: −7.2, P = 0.001; placebo, −2.5). Study 3 included iloperidone 12 to 16 mg/d, risperidone 6 to 8 mg/d, and placebo. The results on the primary efficacy variable, reduction in the BPRS score, was not significant for the 12 to 16 mg/d group versus placebo (−7.1 vs −5.0; P = 0.09), but was significant for the 20 to 24 mg/d iloperidone group (−8.6 vs −5.0; P = 0.01) and for the risperidone group (−11.5 vs 5.0; P < 0.001). A 52-week maintenance trial included iloperidone versus haloperidol as an active control. The primary efficacy variable was time to relapse. Comparison of mean time to relapse of the 2 arms showed no significant difference. The most common adverse events (AEs) associated with iloperidone were dizziness (5.1%–23.2%), dry mouth (5.2%–10.4%), somnolence (4%–13%), and dyspepsia (4.8%–7.8%). AEs appeared dose related. Prescribing information recommends a starting dosage of 1 mg twice daily and then titrated over 7 days to reach a target dosage of 12 to 24 mg/d. The titration is necessary to reduce the risk of orthostatic hypotension-related dizziness. Conclusions Data support that when titrated slowly to a therapeutic dosage, iloperidone is generally well tolerated, has a favorable safety profile, and is an effective treatment option in patients with schizophrenia. Its place in therapy and performance in a typical patient population remain to be established. Slow initial titration and twice-daily dosing are potential disadvantages.

Milnacipran for the management of fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a widespread pain condition associated with fatigue, cognitive dysfunction, sleep disturbance, depression, anxiety, and stiffness. Milnacipran is one of three medications currently approved by the Food and Drug Administration in the United States for the management of adult FMS patients. This review is the second in a three-part series reviewing each of the approved FMS drugs and serves as a primer on the use of milnacipran in FMS treatment including information on pharmacology, pharmacokinetics, safety and tolerability. Milnacipran is a mixed serotonin and norepinephrine reuptake inhibitor thought to improve FMS symptoms by increasing neurotransmitter levels in descending central nervous system inhibitory pathways. Milnacipran has proven efficacy in managing global FMS symptoms and pain as well as improving symptoms of fatigue and cognitive dysfunction without affecting sleep. Due to its antidepressant activity, milnacipran can also be beneficial to FMS patients with coexisting depression. However, side effects can limit milnacipran tolerability in FMS patients due to its association with headache, nausea, tachycardia, hyper- and hypotension, and increased risk for bleeding and suicidality in at-risk patients. Tolerability can be maximized by starting at low dose and slowly up-titrating if needed. As with all medications used in FMS management, milnacipran works best when used as part of an individualized treatment regimen that includes resistance and aerobic exercise, patient education and behavioral therapies.

Duloxetine for the management of fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a widespread pain condition associated with a wide range of additional symptoms including fatigue, insomnia, depression, anxiety and stiffness. Duloxetine is one of three medications currently FDA approved for use in FMS management. Duloxetine is a mixed serotonin and norepinephrine reuptake inhibitor (SNRI) that functions by increasing central nervous system levels of serotonin and norepinephrine. This review is a primer on use of duloxetine in FMS management and includes information on pharmacology and pharmacokinetics, a review of the three duloxetine FMS treatment trials currently in publication, a discussion of the safety and tolerability of duloxetine, and patient-focused perspectives on duloxetine use in FMS management. Duloxetine has proven efficacy in managing pain and mood symptoms in adult FMS patients with and without major depressive disorder. However, due to side effects, duloxetine must be used with caution in patients with fatigue, insomnia, gastrointestinal complaints, headache, cardiovascular disease, bleeding-risk, and in those 24 years of age and younger due to risk of suicidality. Duloxetine use should be avoided in patients with liver disease or alcoholics. As with all medications, duloxetine is best used as part of an individualized regimen that includes nonpharmacologic modalities of exercise, education and behavioral therapies.

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine

Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O-desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N-desmethylvenlafaxine (NDV). The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1.8 and the 10th and 90th percentiles 0.3 and 5.2, respectively. Individuals with ODV/V ratios below 0.3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5.2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1.1 +/- 0.8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4.8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0.3 had more side effects (P < 0.005) and reduced serum concentrations of sodium (P < 0.05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.

Open Trial of Pindolol in the Treatment of Fibromyalgia

Evidence suggests that fibromyalgia is related to both chronic sympathetic hyperactivity and decreased levels of serotonin. To examine the efficacy of pindolol, a mixed serotonin (5-HT)(1A) presynaptic autoreceptor/beta-adrenergic receptor antagonist, in the treatment of fibromyalgia. An open trial was conducted using 20 female patients who met the American College of Rheumatology criteria for fibromyalgia. Treatment was initiated with pindolol 7.5 mg/day and titrated to a maximum dose of 15 mg/day for a total of 90 days. Primary outcome measures were tender point analysis and the Fibromyalgia Impact Questionnaire (FIQ). Anxiety and depression were measured with the Hamilton Depression and Anxiety Scales and Beck Depression Inventory. There was significant improvement in primary outcome measures, including Tender Point Count (mean +/- SD, 16.3 +/- 2.2 vs 12.3 +/- 5.0; F = 8.9; p < 0.001), Tender Point Score (24.4 +/- 5.7 vs 17.5 +/- 9.4; F = 7.8; p < 0.001), and FIQ (45.3 +/- 10.8 vs 35.0 +/- 15.0; F = 5.6; p < 0.005). The depression and anxiety scores did not change significantly among women who completed the study, while the impact on cardiovascular parameters was clinically insignificant. While the current results are encouraging, further studies are needed to determine whether pindolol might be effective in the treatment of fibromyalgia. Limitations of this study include small group size and lack of placebo control.

Atypical Experience: A Case Series of Pediatric Aripiprazole Exposures

Background: Aripiprazole is a new psychotropic agent that possesses a unique pharmacologic profile. The drug demonstrates mixed dopamine and serotonin agonist-antagonist activity and has been labeled a third-generation antipsychotic and dopamine-serotonin system stabilizer. Overdose experience is limited, especially in pediatrics. Case Series: Of five pediatric cases identified, toxicity was mainly evident in younger patients. A 2-year-old who ingested 40 mg experienced vomiting and significant lethargy lasting approximately 30 h. A 6-year-old who received two doses of aripiprazole therapeutically experienced lethargy, drooling, and flaccid facial muscles which improved with diphenhydramine. Two adolescents remained asymptomatic despite doses of 120 mg and 300 mg while a third adolescent with an unknown dose experienced transient lethargy. Conclusion: Aripiprazole is capable of producing marked lethargy and gastrointestinal upset in pediatric patients. Adolescents in this series experienced only minor, if any, clinical effects. Major clinical effects, i.e., seizures, dysrhythmias, were not reported in this series.

Opioid and monoamine systems mediate the discriminative stimulus of tramadol in rats

We analyzed the ability of the mu opioid peptide receptor ligands morphine and naloxone and several antidepressant drugs that are serotonin (fluoxetine), noradrenaline (reboxetine), mixed serotonin and noradrenaline (milnacipram and venlafaxine), dopamine (nomifensine) reuptake inhibitors, as well as roxindole (a nonselective drug) to substitute for, or alter, tramadol discrimination. Male Wistar rats were trained to discriminate tramadol (20 mg/kg) from saline in a two-choice water-reinforced paradigm. Out of the drugs studied, only morphine substituted for tramadol. In combination experiments, naloxone (0.1–1 mg/kg) attenuated the stimulus effects of tramadol (20 mg/kg) and the substitution evoked by morphine (2 mg/kg). Milnacipram (10 mg/kg) or reboxetine (10 mg/kg) enhanced the effects of tramadol (2.5–10 mg/kg); the other antidepressant drugs used failed to modulate tramadol discrimination. Our results indicate that tramadol can be used as a stimulus cue in rats, and that mu opioid peptide mechanisms are involved in its effects, while noradrenergic uptake inhibitors can enhance tramadol discrimination.