Titration Schedule Research Articles

Safety of Two Cluster Schedules for Subcutaneous Immunotherapy in Allergic Rhinitis or Asthma Patients Sensitized to Inhalant Allergens

Background: Subcutaneous immunotherapy (SCIT) usually requires a long titration phase, which can be associated with various adverse events (AEs). Objectives: It was the aim of this study to determine the safety of 2 cluster regimens for SCIT in patients with allergic rhinitis, with or without mild or moderate allergic asthma, who were sensitized to grass and/or tree pollen, or house dust mites (HDM). Patients and Methods: Adult patients were included in a European, open-label, prospective trial. Pollen-allergic patients received grass pollen, grass and olive pollen, or hazel, alder and birch pollen according to a 3-week titration cluster. HDM-allergic patients received HDM extract according to a 2-week titration cluster. The safety of the titration phase was assessed in terms of local and systemic AEs. Results: The safety analysis included 157 patients: 110 received pollen and 47 HDM extract. During the cluster titration, 248 AE episodes were reported in the pollen group and 113 in the HDM group; these were mainly local reactions. Around one third of patients (30.9% pollen and 38.3% HDM) did not experience any AE. In most cases (67.1% of pollen and 71.1% of HDM patients), AEs did not lead to a change in titration schedule. No anaphylactic reaction or other serious life-threatening systemic AEs were reported. Only 2 patients in the HDM group discontinued treatment because of AEs. Conclusions: Rapid cluster titration was well tolerated in adults with allergic rhinitis, with or without mild to moderate allergic asthma, due to pollen or HDM. This short-titration, high-dose cluster regime may allow better patient compliance and cost savings.

Activation Adverse Events Induced by the Selective Serotonin Reuptake Inhibitor Fluvoxamine in Children and Adolescents

The aim of this study was to examine the prevalence of activation cluster adverse events (AC-AEs) in youths treated with the selective serotonin reuptake inhibitor (SSRI) fluvoxamine for anxiety and the relationship of AC-AEs to SSRI blood levels. Data from the Research Units on Pediatric Psychopharmacology (RUPP) Anxiety Study were examined for 45 youths (22 active fluvoxamine, 23 placebo) treated for Diagnostic and Statistical Manual for Mental Disorders, 4(th) edition (DSM-IV) anxiety disorders at the Johns Hopkins University site with an 8-week forced-flexible titration schedule. As part of the double-blind placebo-controlled trial, AC-AEs were recorded by clinicians at weekly patient visits. AC-AEs were defined as hyperactivity, activation, and disinhibition. Demographic characteristics, daily doses, and week-8 blood levels were examined in relation to the presence of AC-AEs. The prevalence of AC-AE and time to first event were established for those who experienced this side effect. AC-AEs were found in 10 of 22 participants (45%) receiving fluvoxamine and only 1 of 23 in the placebo group (4%). The onset of AC-AEs occurred from week 1 to week 8, with the majority occurring at or before week 4. The mean fluvoxamine blood level at week 8 in subjects with AC-AEs was higher than in subjects without AC-AEs (n = 16, t = -2.61, p = 0.04). Neither the age of the participants nor family history of bipolar or anxiety disorder differed between those who did and did not develop an AC-AE. AC-AEs were common side effects of fluvoxamine, often appeared during the first 8 weeks of treatment, and were associated with higher fluvoxamine blood levels. Close monitoring for AC-AEs, not only when initiating SSRI treatment but also throughout dose titration, is recommended for early identification of activation.

Feasibility of a slower lamotrigine titration schedule for bipolar depression: a naturalistic study

The development of a skin rash is often associated with a rapid escalation of lamotrigine dose. We used lamotrigine to treat 259 patients with Diagnostic and Statistical Manual of Mental Disorders, 4th edition, bipolar depression using either the standard titration schedule (n=132) or a slower titration schedule (n=127) and compared the clinical efficacy and safety of both groups. Clinical efficacy of lamotrigine treatment was assessed using changes in the Clinical Global Impression Scale for Bipolar Disorder-Modified scores during the course of the 12-week treatment. A significant reduction of the Clinical Global Impression Scale for Bipolar Disorder-Modified score was observed in both groups and the effect size was large for both groups (standard, 0.75; slower, 0.71). A mixed-effect model of repeated measurement revealed an increased rate of improvement in the standard titration group that was significant during the first 5 weeks (P<0.001) but became nonsignificant by the final 7 weeks of treatment. The statistically significant reduction in the development of rashes (P=0.005) was a major advantage for patients in the slower titration group. Although the standard titration schedule generally led to faster recovery from depressive symptoms, the slower titration schedule may be an option for patients with a high risk of rash development.

Antiepileptic drugs and psychopathology of epilepsy: an update

Anti-epileptic drugs (AEDs) continue to be the mainstay of epilepsy treatment, but the benefits of seizure control need to be weighed carefully against possible adverse effects, which can include behavioral problems and psychiatric disorders. In this paper, the associations between AEDs and psychosis, depression and behavioral changes are reviewed. The concept of forced normalization and its clinical counterpart, alternative psychosis, are also discussed. Depression seems to be linked with AEDs potentiating GABAergic neurotransmission in patients with limbic system abnormalities such as hippocampal sclerosis. Psychoses have been described as associated with several of the new AEDs, and they are often seen in a setting in which previously refractory patients suddenly become seizure-free. In general terms, the use of AEDs in monotherapy, adopting slow titration schedules and low doses when possible, can significantly reduce the occurrence of behavioral adverse effects. A previous history of psychiatric disorder or a familial predisposition are important risk factors and should be always considered when choosing the appropriate AED.

Effectiveness and tolerability of rufinamide in children and adults with refractory epilepsy: First European experience

The aim of the study was to explore the effectiveness and tolerability of rufinamide in a heterogeneous group of patients with refractory epilepsies in Europe, immediately after the drug became available as an orphan drug for the adjunctive treatment of Lennox-Gastaut syndrome (LGS). This observational study was conducted as a collection of retrospective data from multiple centers in Germany and Austria. Clinical course in patients treated with rufinamide was documented. Initial dosage and titration schedule of rufinamide were at the discretion of the treating physician according to medical need. The observation period was 12 weeks. Effectiveness was evaluated by comparing the frequency of seizures with limitations to the countability between baseline and the last 4-week period of observation. The study population consisted of 45 children and 15 adults (mean age: 14.5+/-11.6 years, range: 1-50) with various severe and inadequately controlled epilepsy syndromes, that is, LGS (n=31), idiopathic generalized epilepsy syndromes (n=5), cryptogenic unclassified generalized epilepsy (n=7), and partial epilepsy (n=17). The response rate (50% reduction in countable seizures) was 46.7% (28 of 60 patients) in total; 25.0% experienced a 75% reduction in seizure frequency and 21.7% experienced a 50-75% reduction. Complete seizure control was achieved by 8.3%. The highest response rate was observed in patients with LGS (17/31, 54.8%), and the lowest in patients with partial epilepsy (4/17, 23.5%). Response rate in patients with unclassified generalized epilepsy was 42.8% (3/7 patients). A total of 67 adverse events were reported by 35 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (13.3%), and loss of appetite (10.0%). No serious adverse events were observed. These preliminary data suggest that rufinamide may be effective and well tolerated in the treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures. The results of our study suggest that the efficacy of rufinamide in patients with generalized epilepsy might be comparable to that in patients with LGS, whereas rufinamide was less effective in patients with partial epilepsy.

Challenges of Treatment Adherence in Older Patients with Parkinson’s Disease

Patient adherence to a medication regimen is critical to treatment outcome, quality of life and future healthcare costs. For elderly patients with Parkinson's disease, obstacles to adherence can be particularly complex. Beyond age-related and economic factors, elderly patients with Parkinson's disease often require complicated dosing or titration schedules and have multiple co-morbidities that necessitate administration of therapies from multiple drug classes. In addition, neuropsychiatric disturbances and cognitive impairment, which are often part of the disease process, can affect adherence, as can variable responses to anti-parkinsonian agents as the disease progresses. Several recent studies in patients with Parkinson's disease point to the need for establishing good adherence patterns early and maintaining these throughout the course of treatment. To achieve optimal adherence in elderly patients with Parkinson's disease, a combination of pharmacological and non-pharmacological approaches appears to be the best strategy for success. Examples include a strong provider-patient relationship, educational intervention by phone or face-to-face contact, simplified dosing and administration schedules, management and understanding of medication adverse events, and the use of adherence aids such as pill boxes and hour-by-hour organizational charts. Research into new avenues that include improved drug monitoring, pharmacogenetics and neuroprotective regimens may give rise to better adherence in elderly patients with Parkinson's disease in the future.

P01-141 Is speed of onset of anti-anxiety efficacy with pregabalin influenced by starting dose?

Objective:There appears to be no dose-response effect for pregabalin at doses of 300-600 mg, and a modest dose-response effect in the range of 150-300 mg. The goal of the current investigation was to determine the effect of the starting dose on the speed of onset of anxiolytic efficacy.Methods:Data were analyzed from 7 trials of outpatients with DSM-IV GAD and a HAM-A total score ≥18. Starting doses of pregabalin ranged from 100 mg (N=301) or 150 mg (N=104), to 200 mg (N=167) and 300 mg (N=388). Assessment of early improvement included the HAM-A total score and CGI-Severity and Improvement scores.Results:The mean Week 1 HAM-A change score was similar for a starting dose of 200 mg/d with no titration (-8.24) when compared to patients who started on 200 mg/d and then titrated up to 400 mg/d on Day 4 (-8.64). The mean Week 1 HAM-A change score was somewhat higher for patients started on 300 mg/d, and then titrated to 450 mg/d on Day 4/5 (-8.84) when compared to patients started on a lower (100/150 mg/d) dose and titrated on Day 5 to 400/450 mg/d (-7.32). Starting on a dose of 300 mg/d with no titration resulted in an intermediate Week 1 change score (-7.87). The interaction of starting dose and titration schedule with baseline anxiety severity will be summarized in detail.Conclusion:The initial dose of pregabalin appears to have only a weak effect on the speed of onset of anxiolytic improvement.

Phase I Study of ON 01910.Na, a Novel Modulator of the Polo-Like Kinase 1 Pathway, in Adult Patients With Solid Tumors

We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G(2)/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1). Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1. Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose cohort (3,120 mg) was expanded to six assessable patients. Toxicities were skeletal, abdominal, and tumor pain; nausea; urge to defecate; and fatigue. Hematologic toxicity was infrequent and mild. ON 01910.Na pharmacokinetics were characterized by a rapid distribution phase (distribution half-life, 1 hour) and a relatively slow elimination phase (elimination half-life, 27 hours). A refractory ovarian cancer patient had an objective response after four cycles and remained progression free for 24 months. ON 01910.Na showed a distinct but moderate toxicity pattern. The recommended phase II dose of ON 01910.Na with this schedule of administration is 3,120 mg. Single-agent activity was documented in an ovarian cancer patient.

Body Dysmorphic Disorder: Treating an Underrecognized Disorder

“Mr. H,” a 33-year-old single white male, presented with preoccupations focused on his “thinning” hair, facial “acne,” and “short” fingers. He began to worry excessively about his appearance at age 15, focusing at that time on his “pale” skin and “uneven” cheekbones. Mr. H described his appearance preoccupations as “severely upsetting,” but he was too embarrassed to reveal them to family or friends. Even though he looked normal to others, Mr. H was “100% convinced” that these body areas appeared “abnormal and deformed,” although in the past he had sometimes thought that “maybe I don't look so bad.” He believed that other people took special notice of him and “laugh at me behind my back because I look so ugly.” Mr. H spent 5 to 6 hours a day thinking about his perceived appearance flaws. He also performed compulsive behaviors for 4 to 5 hours a day, which included excessive mirror checking, comparing his appearance with that of other people, wearing and frequently adjusting a baseball cap to cover his hair, picking his skin to remove tiny blemishes, and searching the Internet for acne and hair loss treatments. Mr. H's appearance preoccupations and compulsive behaviors made it difficult to concentrate on his job as a store clerk and often made him late for work. In the past few weeks, he had missed work several times because he thought his skin looked particularly bad on those days. Mr. H avoided many social events with family and friends as well as sexual intimacy with his girlfriend because of shame over how he looked. In addition, he reported depressed mood, anhedonia, feelings of worthlessness, and passive suicidal ideation, and he had attempted suicide 5 years ago. He attributed his depressive symptoms and suicidal thinking to his appearance concerns, stating, “If I didn't look like such a freak, I wouldn't feel so hopeless and depressed.” Mr. H had received treatment from a dermatologist for his acne concerns, which did not diminish his preoccupations. He had never received psychiatric treatment and was ambivalent about trying it because, as he stated, “my appearance problems are real.”

216: Incidence of Flushing Decreases Over Time During Long-Term Therapy with a Novel Combination of Niacin Extended-Release with Simvastatin

Synopsis: Current evidence-based guidelines identify niacin as an important adjunct intervention, along with a statin, in high-risk patients with multiple lipid abnormalities. Perceptions regarding niacin-induced flushing limit its use. To date, however, no study has examined the extent to which patients who flush upon initiation of niacin continue to do so with continued therapy. Purpose: In this 52-week study (OCEANS), the incidence of flushing was evaluated over the duration of treatment in patients who experienced flushing during the initial 12 weeks of therapy with a novel, proprietary, niacin extendedrelease (NER) and simvastatin combination (NER/S). Methods: Patients were randomized to a variable titration schedule of NER/S, attaining a maximum dose of 2000/40 mg/day at 13 weeks. Total treatment duration was 24 to 52 weeks. Only patients who flushed during weeks 1–12 and completed a flushing log for weeks 1–12 and either weeks 13–24 or 41–52 were included in this post-hoc analysis. Concomitant treatment with aspirin/NSAIDS was allowed, though not mandated. Results: Flushing during the first 12 weeks of therapy occurred in 351 of 509 (71%) of patients. Of these patients, 45.8% (108 out of 236) did not experience flushing during weeks 13–24 although the dose of NER/S was increased to 2000/40 mg/day at the beginning of week 13 for 50% of patients. Further, 62.5% (75 out of 120) of patients did not experience flushing during weeks 41–52 [Figure]. Notably, 92% of the total flushing episodes in each titration group were rated as mild or moderate in intensity over the 52-week study. Conclusions: The majority of patients who experienced flushing during the initial 12 weeks of NER/S did not continue to experience flushing over the long-term despite continuing to receive NER/S. These results suggest that concerns with flushing over the long-term may be addressed and tolerance to NER-related flushing commonly occurs.

Dosing Atypical Antipsychotics

Atypical antipsychotic treatment strategies have tended to change significantly from the time new drugs are introduced to the market. Because these drugs are associated with so many side effects, dosing strategies are largely based on the avoidance of adverse effects. A great number of issues complicate the task of effectively dosing atypical antipsychotics, including great variability and unpredictability in individual response. This often leads to extensive periods of trial and error as well as patient suffering, while physicians search for an optimum treatment. The mechanisms of action of these drugs are not entirely understood; they can be effective for both psychosis and mood disorders, possibly via actions on different systems or circuits. Furthermore, a resolution to the dilemma of dosing once or twice daily depends on issues of patient compliance and drug efficacy. This supplement puts these issues into perspective by illustrating historical discrepancies in antipsychotic use between clinical trials and practice, discussing individual response variability to antipsychotic treatment, describing current theories of antipsychotic mechanisms of action, and speculating as to the future of antipsychotic treatment strategies. The following unmet needs regarding dosing atypical antipsychotics were revealed following a vigorous assessment of activity feedback, expert faculty assessment, literature review, and through new medical knowledge: (1) although many clinicians generalize that higher doses are associated with greater efficacy and more side effects, the efficacy and tolerability profile for different doses of atypical antipsychotics are far less straightforward than that; (2) physicians continue to face huge issues of patient adherence when treating schizophrenia and bipolar disorder, which may be mitigated by addressing the most troublesome side effects caused by antipsychotics; (3) research on genetics, neurocircuitry, and new treatment methods in schizophrenia is ongoing; clinicians need to be educated on new treatment strategies as data accumulate so that they are prepared to implement these tools once they become available.

Strategy for utilization of new antiepileptic drugs

The paper reviews strategies to incorporate new antiepileptic drugs into the treatment arsenal for patients with epilepsy. Ten new antiepileptic drugs have been developed in the last two decades, making selection of optimal therapy complex; they have not been shown to have better efficacy but generally seem to be better tolerated. Newer antiepileptic drugs offer new opportunities to patients who have not had a favorable response to the old ones. Many new antiepileptic drugs exhibit a broad spectrum of activity while only one of the older ones (valproate) has a broad-spectrum profile. There are therefore more choices when trying to match treatment with epileptic seizures and syndromes. The side-effect profiles of the newer antiepileptic drugs differ from the older ones with fewer systemic reactions and better pharmacokinetics for the most part. Comparative studies are needed to elucidate the specific weaknesses and strengths of each of the new antiepileptic drugs compared with the older ones. Most clinical trials do not help the physician in deciding drug, dose, or titration schedules. Thus the physician needs to understand efficacy spectrum and side-effect profiles of each new antiepileptic drug in order to be able to treat each patient optimally.

Rapid Dosage Titration of Levetiracetam in Children

To report our experience with rapid titration of levetiracetam regimens in children and adolescents who were unresponsive to or intolerant of other antiepileptic drugs. A retrospective chart review was performed to identify patients with childhood epilepsy who underwent a rapid titration to full doses of levetiracetam in 2 weeks or less. Data regarding demographics, disease characteristics, previous use of antiepileptics, levetiracetam dosage titration schedule, and clinical outcomes were collected and analyzed. Eight children (seven girls, one boy) aged 19 months-17 years were identified. The levetiracetam dosage was titrated to full maintenance doses over 2-14 days (mean 10 days). All patients demonstrated greater than 50% reduction in seizure frequency, with six patients (75%) becoming seizure free. Only one patient experienced a clinically significant adverse event. Rapid dosage titration of levetiracetam is feasible and well tolerated in children who require rapid escalation to therapeutic doses.

Lanthanum Carbonate Effectively Controls Serum Phosphate Without Affecting Serum Calcium Levels in Patients Undergoing Hemodialysis

Treating hyperphosphatemia without increasing the calcium load in chronic kidney disease patients on dialysis is important, as conventional treatment frequently results in ectopic calcification. Sevelamer, a monotherapy for hyperphosphatemia is frequently associated with gastrointestinal disorders, often resulting in discontinuation of treatment. Lanthanum carbonate is a novel non-calcium-based phosphate binder for the treatment of chronic kidney disease. Here, its clinical efficacy and safety were assessed in Japanese dialysis patients. A placebo-controlled, randomized, double-blind, parallel group, multicenter study was performed in Japanese dialysis patients. Patients were treated with various dosages of lanthanum carbonate or a placebo daily for six weeks. The primary efficacy endpoint was the change in serum phosphate level from the baseline. Secondary endpoints included achievement rates to target serum phosphate levels and changes in serum calcium levels. Safety was evaluated by the incidence of drug-related and treatment-emergent adverse events. A significant reduction in serum phosphate level was demonstrated for all dosages from Week 1. This dose-dependent effect was also observed in the changes in serum calcium x phosphate product, yet there was no notable difference in serum calcium or serum intact parathyroid hormone levels. The incidence of drug-related adverse events was dose-dependent, with the most common being gastrointestinal symptoms. Lanthanum carbonate effectively controls serum phosphate levels and is generally tolerable to Japanese chronic kidney disease patients on dialysis, as reported for the Caucasian population. The optimal dosage in Japanese patients needs to be confirmed using a flexible-dose titration schedule.

Switching from Neurostimulant Therapy to Atomoxetine in Children and Adolescents with Attention-Deficit Hyperactivity Disorder

This review provides practical information on and clinical reasons for switching children and young people with attention-deficit hyperactivity disorder (ADHD) from neurostimulants to atomoxetine, detailing currently available evidence, and switching options. The issue is of particular relevance following recent guidance from the National Institute for Health and Clinical Excellence and European ADHD guidelines endorsing the use of atomoxetine, along with the stimulants methylphenidate and dexamphetamine, in the management of ADHD in children and adolescents in the UK. The selective norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine, is a non-stimulant drug licensed for the treatment of ADHD in children and adolescents, and in adults who have shown a response in childhood. Following the once-daily morning dose, its therapeutic effects extend through the waking hours, into late evening, and in some patients, through to early the next morning. Atomoxetine may be considered for patients who are unresponsive or incompletely responsive to stimulant treatment, have co-morbid conditions (e.g. tics, anxiety, depression), and have sleep disturbances or eating problems, for patients in whom stimulants are poorly tolerated, and for situations where there is potential for drug abuse or diversion. Atomoxetine has been shown to be effective in relapse prevention and there is suggestion that atomoxetine may have a positive effect on global functioning; specifically health-related quality of life, self-esteem, and social and family functioning. According to one study, approximately 50% of non-responders to methylphenidate will respond to atomoxetine therapy and approximately 75% of responders to methylphenidate will also respond to atomoxetine. Atomoxetine may be initiated by a schedule of dose increases and cross-tapering with methylphenidate. A slow titration schedule with divided doses minimizes the impact of adverse events within the first several weeks of treatment. Atomoxetine may be co-administered with methylphenidate during the switching period without undue concern for adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is necessary). Atomoxetine may be discontinued abruptly and patients may miss the occasional dose without rebound effects or discontinuation syndrome. A trial period of at least 6-8 weeks, perhaps longer, is recommended before evaluation of the overall tolerability and efficacy of atomoxetine. We conclude that patients with ADHD can be switched from neurostimulants, specifically methylphenidate, to atomoxetine, and may benefit from symptom improvement.

Controlled-release fluvoxamine in obsessive-compulsive disorder and social phobia

Specific serotonin reuptake inhibitors are currently recommended as first-line treatments for obsessive-compulsive disorder (OCD) and social phobia or social anxiety disorder (SAD). Fluvoxamine has demonstrated efficacy in both these conditions and has recently been marketed in a controlled-release (CR) formulation in the United States for treatement of OCD and SAD. Three 12-week double-blind, multicenter, randomized, placebo-controlled studies were conducted with this formulation - two in SAD and one in OCD. All three studies showed a robust effect on the key symptoms of OCD and SAD and had broadly comparable efficacy to studies conducted with immediate-release (IR) fluvoxamine. The beneficial effects of fluvoxamine CR were maintained in a 12-week double-blind, randomized extension to one SAD trial. The CR formulation, when compared to its IR counterpart, offers less daily fluctuation in fluvoxamine levels and a more rapid titration schedule; in addition, a more rapid onset of effect may result from these features. Overall, the benefits of the CR formulation, among them the convenience of oncedaily dosing, were achieved without an increased adverse event burden versus the IR form.

Tramadol extended-release formulations in the management of pain due to osteoarthritis

Tramadol is a centrally acting, synthetic analgesic. Its mechanism of action involves weak binding to the μ-opioid receptors and inhibition of reuptake of both norepinephrine and serotonin. It has been used to treat moderate-to-severe pain for 30 years in Europe and more than 10 years in the USA. Initially available in immediate-release form (dosing four- to six-times daily), in recent years, a variety of once-daily formulations have been developed utilizing different extended-release technologies, which provide different pharmacokinetic characteristics (time to reach therapeutic plasma levels, time to steady state and plasma levels at 24 h), leading to different clinical implications (e.g., titration schedule, time to onset and adverse events). This review addresses the efficacy and safety of the four marketed once-daily formulations with published data in studies on osteoarthritis. Analgesic efficacy and safety results from double-blind clinical studies utilizing 100–400 mg daily doses of these once-daily formulations have been published. Most subjects took tramadol 200 or 300 mg/day. Each once-daily formulation demonstrated statistically superior efficacy compared with placebo or similar efficacy to immediate-release or twice-daily tramadol. Availability of short- and long-term safety data varies among the formulations. Generally, adverse events are typical of tramadol (constipation, nausea, dizziness and somnolence). Descriptively, a trend to comparable or lower incidence and severity of adverse events seems apparent with the various once-daily formulations. Tramadol once-daily formulations are more effective than placebo and at least as effective and well tolerated as immediate-release formulations in the treatment of pain due to osteoarthritis, and offer a reduced dosing regimen, which is especially valuable in elderly patients.

Augmentation of Aripiprazole with Low‐Dose Clozapine

An issue under much clinical debate is whether treatment with two antipsychotic agents simultaneously is advantageous for optimizing response in patients whose previous monotherapy with antipsychotic agents has failed. Minimal evidence supports treatment with multiple antipsychotics, even when the agents have different mechanisms of action. The standard of care for treating schizophrenia is to first use monotherapy of adequate dosage and duration, including a trial of clozapine before adding a second agent. We report the case of a 32-year-old man whose monotherapy with various antipsychotic agents failed. During attempted conversion from aripiprazole to clozapine, the patient experienced a significant reduction in psychiatric features. Despite this improvement, the patient became resistant to the clozapine titration schedule due to complaints of sedation. Aripiprazole combined with low-dose clozapine as maintenance therapy resulted in a positive clinical outcome despite a clozapine serum level that is generally considered subtherapeutic. This case emphasizes the importance of making interventions based on individual patient response.

Donepezil in the Treatment of Severe Alzheimer’s Disease

Donepezil hydrochloride is a reversible acetylcholinesterase inhibitor used in the treatment of Alzheimer’s disease (AD). In 2006, the US FDA approved donepezil for the treatment of severe AD. Consequently, donepezil became the first drug approved for the treatment of all three stages (mild, moderate and severe) of AD. Numerous clinical trials attest not only to the safety and tolerability of donepezil, but also to it’s ability to significantly provide benefits in memory, cognition and activities of daily living for people suffering from severe AD. Side effects associated with donepezil use are generally regarded as mild and transient, and are often associated with the cholinergic properties of the drug. Such side effects consist mainly of gastrointestinal complaints that are sometimes alleviated by slowing down the titration schedule while aiming to reach a target dose. Although donepezil is regarded as an efficacious treatment capable of slowing the progression of symptoms associated with AD, the scientific and medical worlds continue to search for methods of prevention and alternative treatments, in an effort to one day discover a cure for this devastating disease.

Clinical predictors of therapeutic response to clozapine in a sample of Turkish patients with treatment-resistant schizophrenia

Background Several lines of evidence suggest that clozapine is more effective than both first- and second-generation antipsychotic drugs in treatment-resistant schizophrenia (TRS). However, clinicians appear to be hesitant to prescribe this drug. It would therefore be extremely valuable if predictors of response to clozapine could be identified. The aim of this study was to evaluate the predictive factors of clinical responses to clozapine in a group of Turkish patients with TRS. Methods This was a 16-week uncontrolled open study carried out among 97 TRS patients (80 males and 17 females; DSM-IV diagnosis). All patients fulfilled the criteria for refractory schizophrenia according to the UK guidelines for the National Institute of Clinical Excellence (NICE). After all previous antipsychotic medications had run their course, the patients were started on clozapine according to a standardized titration and dosage schedule. Psychopathology was evaluated before the initiation of clozapine therapy and once every 4 weeks using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment for Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. Results Of the TRS patients on clozapine, 55.7% achieved a clinical response, defined as at least a 20% decrease in BPRS. We observed a favorable effect of clozapine on both positive and negative symptoms. Logistic regression analysis showed that a good clozapine response was more likely when schizophrenia began at a later age, when negative symptoms were severe, and when patients had an early response at 4 weeks. Conclusion A combination of demographic, baseline clinical, and acute treatment response variables may accurately predict response to clozapine in TRS. Priority should be given to initiating clozapine at the earliest phase of TRS, especially for patients with evident negative symptoms.