Showing papers in "Neuropsychiatric Disease and Treatment in 2010"

Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine.

Abstract: These studies investigated the absorption and metabolic conversion of lisdexamfetamine dimesylate (LDX), a prodrug stimulant that requires conversion to d-amphetamine for activity. Oral absorption of LDX was assessed in rat portal and jugular blood, and perfusion of LDX into isolated intestinal segments of anesthetized rats was used to assess regional absorption. Carrier-mediated transport of LDX was investigated in Caco-2 cells and Chinese hamster ovary (CHO) cells expressing human peptide transporter-1 (PEPT1). LDX metabolism was studied in rat and human tissue homogenates and human blood fractions. LDX was approximately10-fold higher in portal blood versus systemic blood. LDX and d-amphetamine were detected in blood following perfusion of the rat small intestine but not the colon. Transport of LDX in Caco-2 cells had permeability apparently similar to cephalexin and was reduced with concurrent PEPT1 inhibitor. Affinity for PEPT1 was also demonstrated in PEPT1-transfected CHO cells. LDX metabolism occurred primarily in whole blood (rat and human), only with red blood cells. Slow hydrolysis in liver and kidney homogenates was probably due to residual blood. The carrier-mediated absorption of intact LDX, likely by the high-capacity PEPT1 transporter, and subsequent metabolism to d-amphetamine in a high-capacity system in blood (ie, red blood cells) may contribute to the consistent, reproducible pharmacokinetic profile of LDX.

The relationship between depression, anxiety, and cardiovascular outcomes in patients with acute coronary syndromes

Abstract: Depression and anxiety occur at high rates among patients suffering an acute coronary syndrome (ACS). Both depressive symptoms and anxiety appear to adversely affect in-hospital and long term cardiac outcomes of post-ACS patients, independent of traditional risk factors. Despite their high prevalence and serious impact, mood and anxiety symptoms go unrecognized and untreated in most ACS patients and such symptoms (rather than being transient reactions to ACS) persist for months and beyond. The mechanisms by which depression and anxiety are linked to these negative medical outcomes are likely a combination of the effects of these conditions on inflammation, catecholamines, heart rate variability, and endothelial function, along with effects on health-promoting behavior. Fortunately, standard treatments for these disorders appear to be safe, well-tolerated and efficacious in this population; indeed, selective serotonin reuptake inhibitors may actually improve cardiac outcomes. Future research goals include gaining a better understanding of the combined effects of depression and anxiety, as well as definitive prospective studies of the impact of treatment on cardiac outcomes. Clinically, protocols that allow for efficient and systematic screening, evaluation, and treatment for depression and anxiety in cardiac patients are critical to help patients avoid the devastating effects of these illnesses on quality of life and cardiac health.

Distinguishing between attention-deficit hyperactivity and fetal alcohol spectrum disorders in children: clinical guidelines

Abstract: Fetal alcohol spectrum disorders (FASD) are the physical and neurodevelopmental outcomes of fetal alcohol exposure. The behavioral phenotype of children with FASD includes difficulties with executive function, memory, planning, processing speed, and attention. Although attention deficit hyperactivity disorder (ADHD) is diagnosed in up to 94% of individuals with heavy prenatal alcohol exposure, the exact relationship between FASD and ADHD is unclear. There is some evidence that ADHD in FASD may be a specific clinical subtype and thus may require a different treatment approach. Although traditional behavioral observation scales may not distinguish between the two groups, there is evidence that children with FASD have a different profile on the four-factor model of attention than children with ADHD who do not have FASD. There is a paucity of good scientific evidence on effective interventions for individuals with ADHD and FASD. There is weak evidence that children with FASD and ADHD may have a better response to dexamphetamine than methylphenidate. There is a strong need for larger, high quality studies to examine the relationship between ADHD and FASD and identify effective treatments because management of inattention and hyperactivity may improve learning and ameliorate the common secondary disabilities associated with FASD.

Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease

Abstract: Huntington disease (HD) is a dominantly inherited progressive neurological disease characterized by chorea, an involuntary brief movement that tends to flow between body regions. HD is typically diagnosed based on clinical findings in the setting of a family history and may be confirmed with genetic testing. Predictive testing is available to those at risk, but only experienced clinicians should perform the counseling and testing. Multiple areas of the brain degenerate mainly involving the neurotransmitters dopamine, glutamate, and γ-aminobutyric acid. Although pharmacotherapies theoretically target these neurotransmitters, few well-conducted trials for symptomatic or neuroprotective interventions yielded positive results. Tetrabenazine (TBZ) is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. Some newer antipsychotic agents, such as olanzapine and aripiprazole, may have adequate efficacy with a more favorable adverse-effect profile than older antipsychotic agents for treating chorea and psychosis. This review will address the epidemiology and diagnosis of HD as background for understanding potential pharmacological treatment options. Because TBZ is the only US Food and Drug Administration-approved medication in the United States for HD, the focus of this review will be on its pharmacology, efficacy, safety, and practical uses. There are no current treatments to change the course of HD, but education and symptomatic therapies can be effective tools for clinicians to use with patients and families affected by HD.

Walking impairment in patients with multiple sclerosis: exercise training as a treatment option

Abstract: Multiple sclerosis (MS) is a chronic disease of the central nervous system that culminates in the progression of physical and cognitive disability over time. Walking impairment is a ubiquitous feature of MS and a sentinel characteristic of the later or advanced stages of the disease. This paper presents a conceptual rationale along with empirical evidence for exercise training as a rehabilitation approach for managing walking impairment and improving walking function in persons with MS. Conceptually, MS is associated with a decrease in physical activity, which, in turn, can result in deconditioning across multiple domains of physiological functioning. The resulting deconditioning feeds back and further drives physical inactivity until a threshold is reached that likely initiates the progression of walking impairment in MS. Empirically, physical activity and exercise training have been associated with beneficial effects on walking function in persons with MS. This is based on cross-sectional, longitudinal, and experimental research that included diversity in the breadth of measures of walking, persons with MS, and exercise/physical activity characteristics. Of particular importance, future researchers might consider examining the combinatory effects of exercise training plus pharmacological agents on walking mobility in MS. Collectively, exercise training and physical activity might hold significant potential for the management of progressive mobility disability in MS.

Relationship between hair cortisol concentrations and depressive symptoms in patients with coronary artery disease.

Abstract: Objective Concentrations of cortisol in hair, a novel marker of longer-term cortisol status, were compared in depressed versus nondepressed patients with coronary artery disease (CAD). Methods 20 mg hair samples of 3 cm length were collected from 121 patients attending a cardiac rehabilitation program, 34 of whom suffered from depressive symptoms. Results Controlling for age, gender, coronary artery bypass grafting, history of depression, and time since most recent acute coronary syndrome, cortisol concentrations (P = 0.162) did not predict severity of depression. Younger age (P = 0.003) was a significant predictor of depressive symptoms. Perceived stress was not associated with long-term cortisol concentrations (P = 0.161). Conclusions Cortisol concentrations in hair do not predict depressive symptoms in CAD patients attending cardiac rehabilitation.

Psychiatric comorbidity and suicide risk in patients with chronic migraine

Abstract: The aim of this study was to explore the impact of mental illness among patients with migraine. We performed MedLine and PsycINFO searches from 1980 to 2008. Research has systematically documented a strong bidirectional association between migraine and psychiatric disorders. The relationship between migraine and psychopathology has often been clinically discussed rather than systematically studied. Future research should include sound methodologically-based studies focusing on the interplay of factors behind the relationship between migraine, suicide risk, and mental illness.

Clinical management of behavioral characteristics of Prader–Willi syndrome

Abstract: Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by an abnormality on the long arm of chromosome 15 (q11–q13) that results in a host of phenotypic characteristics, dominated primarily by hyperphagia and insatiable appetite. Characteristic behavioral disturbances in PWS include excessive interest in food, skin picking, difficulty with a change in routine, temper tantrums, obsessive and compulsive behaviors, and mood fluctuations. Individuals with PWS typically have intellectual disabilities (borderline to mild/moderate mental retardation) and exhibit a higher overall behavior disturbance compared to individuals with similar intellectual disability. Due to its multisystem disorder, family members, caregivers, physicians, dieticians, and speech-language pathologists all play an important role in the management and treatment of symptoms in an individual with PWS. This article reviews current research on behavior and cognition in PWS and discusses management guidelines for this disorder.

Faster return to work after psychiatric consultation for sicklisted employees with common mental disorders compared to care as usual. A randomized clinical trial

Abstract: Introduction: Return to work (RTW) of employees on sick leave for common mental disorders may require a multidisciplinary approach. This article aims to assess time to RTW after a psychiatric consultation providing treatment advice to the occupational physician (OP) for employees on sick leave for common mental disorders in the occupational health (OH) setting, compared to care as usual (CAU). Methods: Cluster randomized clinical trial evaluating patients of 12 OPs receiving consultation by a psychiatrist, compared to CAU delivered by 12 OPs in the control group. 60 patients suffering from common mental disorders and >= six weeks sicklisted were included. Follow up three and six months after inclusion. Primary outcome measure was time to RTW. Intention-to-treat multilevel analysis and a survival analysis were performed to evaluate time to RTW in both groups. Results: In CAU, referral was the main intervention. Both groups improved in terms of symptom severity and quality of life, but time to RTW was significantly shorter in the psychiatric consultation group. At three months follow up, 58% of the psychiatric consultation group had full RTW versus 44% of the control group, a significant finding (P = 0.0093). Survival analysis showed 68 days earlier RTW after intervention in the psychiatric consultation group (P = 0.078) compared to CAU. Conclusion: Psychiatric consultation for employees on sick leave in the OH setting improves time to RTW in patients with common mental disorders as compared to CAU. In further research, focus should be on early intervention in patients with common mental disorders on short sick leave duration. Psychiatric consultation might be particularly promising for improvement of RTW in those patients.

The societal costs of insomnia

Abstract: OBJECTIVE: Insomnia can be broadly defined as difficulty initiating or maintaining sleep, or sleep that is not refreshing or of poor quality with negative effect on daytime function. Insomnia can be a primary condition or comorbid to an underlying disorder. Subjective measures of insomnia used in population studies, usually based on complaints of unsatisfactory sleep, put the prevalence at about 10%. Insomnia is more common in the elderly and in women, and is often associated with medical and psychiatric disorders. This review examines the measures used to assess quality of sleep (QOS) and daytime functioning and the impact of insomnia on society using these measures. METHODS: Literature searches were performed to identify all studies of insomnia (primary and comorbid) in adults (aged 18-64 years) and the elderly (aged ≥ 65 years) with baseline and/or outcomes relating to QOS or daytime functioning. The impact of poor QOS on quality of life (QOL), psychomotor and cognitive skills, health care resource utilization, and other societal effects was examined. RESULTS: Although definitions and measurement scales used to assess sleep quality vary widely, it is clear that the societal consequences of insomnia are substantial and include impaired QOL and increased health care utilization. The impact of poor QOS and impaired daytime functioning common in insomnia can lead to indirect effects such as lower work productivity, increased sick leave, and a higher rate of motor vehicle crashes. CONCLUSIONS: Insomnia is associated with substantial direct and indirect costs to society. It is almost impossible to separate the costs associated with primary and comorbid insomnia. More studies are required which control for the severity of any primary disorder to accurately evaluate the costs of comorbid insomnia. Development of standardized diagnostic and assessment scales will enable more accurate quantification of the true societal burden of insomnia and will contribute to greater understanding of this disorder. Language: en

Long-acting injectable antipsychotics: focus on olanzapine pamoate.

Abstract: Medication non-adherence in patients with schizophrenia continues to be a significant problem and threatens successful treatment outcomes. Medication non-adherence is often associated with negative consequences, including symptom exacerbation, more frequent emergency room visits, re-hospitalizations and relapse. Long-acting injectable (LAI) forms of antipsychotics allow for rapid identification of non-adherence, obviate the need for the patient to take the medication on a daily basis and increase adherence to some significant degree. Eli Lilly has developed a long-acting depot formulation of olanzapine, olanzapine pamoate, which has recently been approved by the FDA for the US market, and which will be reviewed here. Olanzapine LAI appears to be an effective antipsychotic at dosages of 210 mg every 2 weeks, 300 mg every 2 weeks and 405 mg every 4 weeks in patients with acute schizophrenia, and at 150 mg every 2 weeks, 300 mg every 2 weeks and at 405 mg every 4 weeks for the maintenance treatment of stable patients. Oral supplementation appears not to be needed, particularly not at the onset of treatment with the LAI as is necessary with risperidone LAI. Its efficacy is in general comparable to the efficacy seen with oral olanzapine at a corresponding dose. The side effect profile is also comparable to the side effects observed with oral olanzapine, including lower rates of extrapyramidal symptoms, prolactin elevation and cardiovascular side effects, but significant metabolic effects. The latter include significant weight gain, lipid abnormalities and glucose dysregulation. While the injection site adverse events are overall mild, the most significant serious adverse event is the post-injection delirium sedation syndrome (PDSS). While rare, this syndrome results from inadvertent intravascular injection of olanzapine LAI and can cause a range of olanzapine overdose-type of symptoms. Olanzapine LAI needs therefore to be administered by trained personnel in settings where a post-injection observation period for at least 3 hours by medical personnel is available. The overall use of olanzapine LAI will probably be limited by the possibility of a PDSS event. Patients who have a history of good response to oral olanzapine and are in need of assured medication administration may present a good indication for its use, provided that the appropriate mental health delivery setting is available.

Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD)

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a highly disruptive childhood-onset disorder that often persists into adolescence and adulthood. Comorbidity with other problems, such as autism, dyslexia and conduct disorder (CD) is very common. Although little is known about the pathophysiology of ADHD, family, twin and adoption studies have shown that it is highly heritable. Whole genome linkage studies suggest there are no common susceptibility genes of moderate effect size. Most published research has been based on functional candidate gene studies. The most consistent evidence for association with ADHD relates to a dopamine D4 receptor (DRD4) gene variable number tandem repeat (VNTR), a dopamine D5 receptor (DRD5) gene microsatellite and a dopamine transporter (DAT1) gene VNTR. In addition, the catechol-O-methyltransferase (COMT) val158/108 met variant has been shown to increase risk for associated antisocial behavior. The first genome-wide association studies (GWAS) of ADHD have been completed and although larger studies are still required to detect common risk variants, novel risk pathways are being suggested for ADHD. Further research on the contribution of rare variants, larger genome-wide association and sequencing studies and ADHD phenotype refinement is now needed.

Management of depression in elderly stroke patients

Abstract: Poststroke depression (PSD) in elderly patients has been considered the most common neuropsychiatric consequence of stroke up to 6-24 months after stroke onset. When depression appears within days after stroke onset, it is likely to remit, whereas depression at 3 months is likely to be sustained for 1 year. One of the major problems posed by elderly stroke patients is how to identify and optimally manage PSD. This review provides insight to identification and management of depression in elderly stroke patients. Depression following stroke is less likely to include dysphoria and more likely characterized by vegetative signs and symptoms compared with other forms of late-life depression, and clinicians should rely more on nonsomatic symptoms rather than somatic symptoms. Evaluation and diagnosis of depression among elderly stroke patients are more complex due to vague symptoms of depression, overlapping signs and symptoms of stroke and depression, lack of properly trained health care personnel, and insufficient assessment tools for proper diagnosis. Major goals of treatment are to reduce depressive symptoms, improve mood and quality of life, and reduce the risk of medical complications including relapse. Antidepressants (ADs) are generally not indicated in mild forms because the balance of benefit and risk is not satisfactory in elderly stroke patients. Selective serotonin reuptake inhibitors are the first choice of PSD treatment in elderly patients due to their lower potential for drug interaction and side effects, which are more common with tricyclic ADs. Recently, stimulant medications have emerged as promising new therapeutic interventions for PSD and are now the subject of rigorous clinical trials. Cognitive behavioral therapy can also be useful, and electroconvulsive therapy is available for patients with severe refractory PSD.

Cobalamin deficiency, hyperhomocysteinemia, and dementia.

Abstract: INTRODUCTION Although consensus guidelines recommend checking serum B12 in patients with dementia, clinicians are often faced with various questions: (1) Which patients should be tested? (2) What test should be ordered? (3) How are inferences made from such testing? (4) In addition to serum B12, should other tests be ordered? (5) Is B12 deficiency compatible with dementia of the Alzheimer's type? (6) What is to be expected from treatment? (7) How is B12 deficiency treated? METHODS On January 31st, 2009, a Medline search was performed revealing 1,627 citations related to cobalamin deficiency, hyperhomocysteinemia, and dementia. After limiting the search terms, all abstracts and/or articles and other references were categorized into six major groups (general, biochemistry, manifestations, associations and risks, evaluation, and treatment) and then reviewed in answering the above questions. RESULTS The six major groups above are described in detail. Seventy-five key studies, series, and clinical trials were identified. Evidence-based suggestions for patient management were developed. DISCUSSION Evidence is convincing that hyperhomocysteinemia, with or without hypovitaminosis B12, is a risk factor for dementia. In the absence of hyperhomocysteinemia, evidence is less convincing that hypovitaminosis B12 is a risk factor for dementia. B12 deficiency manifestations are variable and include abnormal psychiatric, neurological, gastrointestinal, and hematological findings. Radiological images of individuals with hyperhomocysteinemia frequently demonstrate leukoaraiosis. Assessing serum B12 and treatment of B12 deficiency is crucial for those cases in which pernicious anemia is suspected and may be useful for mild cognitive impairment and mild to moderate dementia. The serum B12 level is the standard initial test: 200 picograms per milliliter or less is low, and 201 to 350 picograms per milliliter is borderline low. Other tests may be indicated, including plasma homocysteine, serum methylmalonic acid, antiparietal cell and anti-intrinsic factor antibodies, and serum gastrin level. In B12 deficiency dementia with versus without pernicious anemia, there appear to be different manifestations, need for further workup, and responses to treatment. Dementia of the Alzheimer's type is a compatible diagnosis when B12 deficiency is found, unless it is caused by pernicious anemia. Patients with pernicious anemia generally respond favorably to supplemental B12 treatment, especially if pernicious anemia is diagnosed early in the course of the disease. Some patients without pernicious anemia, but with B12 deficiency and either mild cognitive impairment or mild to moderate dementia, might show some degree of cognitive improvement with supplemental B12 treatment. Evidence that supplemental B12 treatment is beneficial for patients without pernicious anemia, but with B12 deficiency and moderately-severe to severe dementia is scarce. Oral cyanocobalamin is generally favored over intramuscular cyanocobalamin.

Overview of essential tremor

Abstract: Essential tremor (ET) is one of the most common movement disorders in the world. Despite this, only one medication (propranolol) is approved by the Food and Drug Administration (FDA) to treat it. Fortunately, recent studies have identified some additional medications as treatment of ET. Surgical procedures, such as deep brain stimulation of the ventral intermediate nucleus of the thalamus, offer treatment for refractory tremor. The epidemiology, pathogenesis, and medical and surgical treatment of ET will be discussed in this paper.

Short cognitive behavioral therapy and cognitive training for adults with ADHD – a randomized controlled pilot study

Abstract: In clinical practice, a growing need exists for effective non-pharmacological treatments of adult attention-deficit/hyperactivity disorder (ADHD). Here, we present the results of a pilot study of 10 adults with ADHD participating in short-term individual cognitive- behavioral therapy (CBT), 9 adults participating in cognitive training (CT), and 10 controls. Self-report questionnaires, independent evaluations, and computerized neurocognitive testing were collected before and after the treatments to evaluate change. There were distinctive pre-hypotheses regarding the treatments, and therefore the statistical comparisons were conducted in pairs: CBT vs control, CT vs control, and CBT vs CT. In a combined ADHD symptom score based on self-reports, 6 participants in CBT, 2 in CT and 2 controls improved. Using independent evaluations, improvement was found in 7 of the CBT participants, 2 of CT participants and 3 controls. There was no treatment-related improvement in cognitive performance. Thus, in the CBT group, some encouraging improvement was seen, although not as clearly as in previous research with longer interventions. In the CT group, there was improvement in the trained tasks but no generalization of the improvement to the tasks of the neurocognitive testing, the self- report questionnaires, or the independent evaluations. These preliminary results warrant further studies with more participants and with more elaborate cognitive testing.

Once-monthly paliperidone injection for the treatment of schizophrenia

Abstract: Paliperidone palmitate is a new long-acting antipsychotic injection for the treatment of acute and maintenance therapy in schizophrenia. Paliperidone (9-hydroxyrisperidone) is the major active metabolite of risperidone and acts at dopamine D(2) and serotonin 5HT(2A) receptors. As with other atypical antipsychotics, it exhibits a high 5HT(2A):D(2) affinity ratio. It also has binding activity as an antagonist at α(1)-and α(2) adrenergic receptors and H(1) histaminergic receptors, but has virtually no affinity for cholinergic receptors. Paliperidone palmitate has been shown to be effective in reducing Positive and Negative Syndrome Scale total scores in four short-term trials in acute schizophrenia. It was also effective as maintenance therapy in a long-term trial in which time to recurrence of symptoms was significantly longer in paliperidone-treated patients compared with placebo. In addition, paliperidone was shown to be noninferior to risperidone long-acting injection in one study, but this noninferiority was not established in another longer study comparing the two drugs. Treatment should be initiated with 234 mg on day 1 and 156 mg on day 8, followed by a recommended monthly maintenance dose of 39-234 mg based on efficacy and tolerability. Paliperidone palmitate is generally well tolerated, although it can cause weight gain and a rise in prolactin levels, which is generally greater in women than in men. Overall, paliperidone palmitate may have advantages over other currently available long-acting injections, and therefore may be a useful alternative for the treatment of schizophrenia, although further long-term trials comparing it with active treatments are warranted.

Current Trends in Drug Treatment of Obsessive-Compulsive Disorder

Abstract: This article aims to highlight current trends in the pharmacologic management of obsessive–compulsive disorder (OCD). A systematic search of the electronic database MEDLINE was conducted. The first case report of clomipramine efficacy in the management OCD more than 40 years ago gave new hope for the treatment of this debilitating disorder. Selective serotonin reuptake inhibitors (SSRIs) proved to have a similar efficacy profile compared with clomipramine but had a superior tolerability profile. While many patients with OCD respond to SSRIs or clomipramine, the treatment of those with refractory OCD remains challenging. Different augmentation agents in treatment-resistant OCD have been explored, with antipsychotic agents having the largest supporting evidence base. Nevertheless, new pharmacologic treatment options are required and are under investigation.

Psychiatric diagnoses in patients with burning mouth syndrome and atypical odontalgia referred from psychiatric to dental facilities.

Abstract: Background: Burning mouth syndrome (BMS) and atypical odontalgia (AO) are two conditions involving chronic oral pain in the absence of any organic cause. Psychiatrically they can both be considered as “somatoform disorder”. From the dental point of view, however, the two disorders are quite distinct. BMS is a burning or stinging sensation in the mouth in association with a normal mucosa whereas AO is most frequently associated with a continuous pain in the teeth or in a tooth socket after extraction in the absence of any identifiable cause. Because of the absence of organic causes, BMS and AO are often regarded as psychogenic conditions, although the relationship between oral pain and psychologic factors is still unclear. Some studies have analyzed the psychiatric diagnoses of patients with chronic oral pain who have been referred from dental facilities to psychiatric facilities. No study to date has investigated patients referred from psychiatric facilities to dental facilities. Objective: To analyze the psychiatric diagnoses of chronic oral pain patients, diagnosed with BMS and AO, and referred from psychiatric facilities to dental facilities. Study design: Psychiatric diagnoses and disease conditions of BMS or AO were investigated in 162 patients by reviewing patients’ medical records and referral forms. Psychiatric diagnoses were categorized according to the International Statistical Classification of Disease and Related Health Problems, Tenth Revision. Results: The proportion of F4 classification (neurotic, stress-related, and somatoform disor ders) in AO patients was significantly higher than in BMS patients. BMS patients were more frequently given a F3 classification (mood/affective disorders). However, 50.8% of BMS patients and 33.3% of AO patients had no specific psychiatric diagnoses. Conclusion: Although BMS and AO are both chronic pain disorders occurring in the absence of any organic cause, the psychiatric diagnoses of patients with BMS and AO differ

Insight in bipolar disorder: relationship to episode subtypes and symptom dimensions

Abstract: Background The study of insight in bipolar disorder has received limited attention, despite its potential impact on treatment compliance and prognosis. In the current study we compare insight levels during different phases of bipolar disorder, and consider its relationship to symptoms dimensions and epidemiologic variables.

Tailoring therapeutic strategies for treating posttraumatic stress disorder symptom clusters

Abstract: According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, posttraumatic stress disorder (PTSD) is characterized by three major symptom clusters following an event that elicited fear, helplessness, or horror. This review will examine each symptom cluster of PTSD separately, giving case study examples of patients who exhibit a preponderance of a given symptom domain. We use a translational approach in describing the underlying neurobiology that is relevant to particular symptoms and treatment options, thus showing how clinical practice can benefit from current research. By focusing on symptom clusters, we provide a more specific view of individual patient’s clinical presentations, in order to better address treatment needs. Finally, the review will also address potential genetic approaches to treatment as another form of individualized treatment.

Antipsychotic treatments for the elderly: efficacy and safety of aripiprazole

Abstract: Delusions, hallucinations and other psychotic symptoms can accompany a number of conditions in late life. As such, elderly patients are commonly prescribed antipsychotic medications for the treatment of psychosis in both acute and chronic conditions. Those conditions include schizophrenia, bipolar disorder, depression and dementia. Elderly patients are at an increased risk of adverse events from antipsychotic medications because of age-related pharmacodynamic and pharmacokinetic changes as well as polypharmacy. Drug selection should be individualized to the patient's previous history of antipsychotic use, current medical conditions, potential drug interactions, and potential side effects of the antipsychotic. Specifically, metabolic side effects should be closely monitored in this population. This paper provides a review of aripiprazole, a newer second generation antipsychotic agent, for its use in a variety of psychiatric disorders in the elderly including schizophrenia, bipolar disorder, dementia, Parkinson's disease and depression. We will review the pharmacokinetics and pharmacodynamics of aripiprazole as well as dosing, diagnostic indications, efficacy studies, and tolerability including its metabolic profile. We will also detail patient focused perspectives including quality of life, patient satisfaction and adherence.

Not all partial dopamine D2 receptor agonists are the same in treating schizophrenia. Exploring the effects of bifeprunox and aripiprazole using a computer model of a primate striatal dopaminergic synapse

Abstract: Species differences in physiology and unique active human metabolites contribute to the limited predictive value of preclinical rodent models for many central nervous system (CNS) drugs. In order to explore possible drivers for this translational disconnect, we developed a computer model of a dopaminergic synapse that simulates the competition among three agents and their binding to pre- and postsynaptic receptors, based on the affinities for their targets and their actual concentrations. The model includes presynaptic autoreceptor effects on neurotransmitter release and modulation by presynaptic firing frequency and is calibrated with actual experimental data on free dopamine levels in the striatum of the rodent and the primate. Using this model, we simulated the postsynaptic dopamine D(2) receptor activation levels of bifeprunox and aripiprazole, two relatively similar dopamine D(2) receptor agonists. The results indicate a substantial difference in dose-response for the two compounds when applying primate calibration parameters as opposed to rodent calibration parameters. In addition, when introducing the major human and rodent metabolites of aripiprazole with their specific pharmacological activities, the model predicts that while bifeprunox would result in a higher postsynaptic D(2) receptor antagonism in the rodent, aripiprazole would result in a higher D(2) receptor antagonism in the primate model. Furthermore, only the highest dose of aripiprazole, but not bifeprunox, reaches postsynaptic functional D(2) receptor antagonism similar to 4 mg haloperidol in the primate model. The model further identifies a limited optimal window of functionality for dopamine D(2) receptor partial agonists. These results suggest that computer modeling of key CNS processes, using well-validated calibration paradigms, can increase the predictive value in the clinical setting of preclinical animal model outcomes.

Abnormal auditory forward masking pattern in the brainstem response of individuals with Asperger syndrome

Abstract: Abnormal auditory information processing has been reported in individuals with autism spectrum disorders (ASD). In the present study auditory processing was investigated by recording auditory brainstem responses (ABRs) elicited by forward masking in adults diagnosed with Asperger syndrome (AS). Sixteen AS subjects were included in the forward masking experiment and compared to three control groups consisting of healthy individuals (n = 16), schizophrenic patients (n = 16) and attention deficit hyperactivity disorder patients (n = 16), respectively, of matching age and gender. The results showed that the AS subjects exhibited abnormally low activity in the early part of their ABRs that distinctly separated them from the three control groups. Specifically, wave III amplitudes were significantly lower in the AS group than for all the control groups in the forward masking condition (P < 0.005), which was not the case in the baseline condition. Thus, electrophysiological measurements of ABRs to complex sound stimuli (eg, forward masking) may lead to a better understanding of the underlying neurophysiology of AS. Future studies may further point to specific ABR characteristics in AS individuals that separate them from individuals diagnosed with other neurodevelopmental diseases.

Tinnitus psychopharmacology: A comprehensive review of its pathomechanisms and management.

Abstract: Background: Subjective tinnitus is a frequent, impairing condition, which may also cause neurotransmitter imbalance at the cochlea. Psychopharmacologic agents, although not being the first-line treatment for tinnitus, may modulate cochlear neurotransmission, thereby influencing the subjective tinnitus experience.

Milnacipran: a unique antidepressant?

Abstract: Tricyclic antidepressants (TCAs) are among the most effective antidepressants available, although their poor tolerance at usual recommended doses and toxicity in overdose make them difficult to use. While selective serotonin reuptake inhibitors (SSRIs) are better tolerated than TCAs, they have their own specific problems, such as the aggravation of sexual dysfunction, interaction with coadministered drugs, and for many, a discontinuation syndrome. In addition, some of them appear to be less effective than TCAs in more severely depressed patients. Increasing evidence of the importance of norepinephrine in the etiology of depression has led to the development of a new generation of antidepressants, the serotonin and norepinephrine reuptake inhibitors (SNRIs). Milnacipran, one of the pioneer SNRIs, was designed from theoretic considerations to be more effective than SSRIs and better tolerated than TCAs, and with a simple pharmacokinetic profile. Milnacipran has the most balanced potency ratio for reuptake inhibition of the two neurotransmitters compared with other SNRIs (1:1.6 for milnacipran, 1:10 for duloxetine, and 1:30 for venlafaxine), and in some studies milnacipran has been shown to inhibit norepinephrine uptake with greater potency than serotonin (2.2:1). Clinical studies have shown that milnacipran has efficacy comparable with the TCAs and is superior to SSRIs in severe depression. In addition, milnacipran is well tolerated, with a low potential for pharmacokinetic drug–drug interactions. Milnacipran is a first-line therapy suitable for most depressed patients. It is frequently successful when other treatments fail for reasons of efficacy or tolerability.

Effects of quetiapine on sleep architecture in patients with unipolar or bipolar depression

Abstract: OBJECTIVE To determine the effect of adjunctive quetiapine therapy on the sleep architecture of patients with bipolar or unipolar depression. METHODS This is a prospective, single-blind, repeated measures polysomnographic study. Sleep architecture was analyzed by overnight polysomnography, and subjective sleep quality was measured using the Pittsburgh Sleep Quality Index. The Hamilton Rating Scale for Depression, Montgomery Asberg Depression Rating Scale, Young Mania Rating Scale, and Clinical Global Impression-Severity Scale were employed to quantify changes in illness severity with adjunctive quetiapine treatment. Polysomnographs and clinical measures were administered at baseline, after 2-4 days of treatment, and after 21-28 days of quetiapine treatment. The average dose of quetiapine was 155 mg, ranging from 100-200 mg. RESULTS Adjunctive quetiapine therapy did not significantly alter sleep efficiency, sleep continuity, or Pittsburgh Sleep Quality Index scores. Respiratory Disturbance Index and percentage of total time in rapid eye movement (REM) sleep significantly decreased and the percentage of total time in non-REM sleep, and duration of Stage 2 and non-REM sleep significantly increased after 2-4 days of quetiapine treatment. Illness severity significantly decreased over time. CONCLUSIONS Adjunctive quetiapine treatment alters sleep architecture in patients with major depressive disorder or bipolar disorder, which may partially explain its early antidepressant properties. Changes in sleep architecture are more robust and significant within two to four days of starting treatment.

Lacosamide for the prevention of partial onset seizures in epileptic adults.

Abstract: Lacosamide is a newly registered antiepileptic drug with dual mechanisms of action. It selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It also binds to a collapsing-response mediator protein-2, CRMP2. Lacosamide has a favorable pharmacokinetic profile; is rapidly and completely absorbed, has a relatively long elimination half-life of 13 hours which allows twice-daily administration, linear pharmacokinetics, and has low potential for drug interactions and renal elimination. Both oral and intravenous formulations of lacosamide are being developed. In placebo-controlled clinical trials, lacosamide was effective in seizure reduction as adjunctive therapy in patients with uncontrolled partial-onset seizures. Lacosamide was generally well tolerated. The most frequently reported adverse events in placebo-controlled trials were dizziness, headache, nausea, and diplopia. Intravenous lacosamide has a comparably good safety profile.

Profile of olanzapine long-acting injection for the maintenance treatment of adult patients with schizophrenia

Abstract: Olanzapine long-acting injection (OLAI) is a crystalline salt composed of olanzapine and pamoic acid, which permits a depot intramuscular formulation of olanzapine. The half-life of olanzapine pamoate is 30 days, and its steady state is reached approximately at 12 weeks. Oral supplementation of olanzapine is not required during OLAI initiation, according to Eli Lilly recommendations, although a study indicated that ≥60% of D(2) receptor occupancy was reached only by the fifth injection cycle. To date, a short-term, placebo-controlled study of 8 weeks in acutely ill patients and a long-term, controlled trial of 24 weeks in stabilized patients have been conducted. In both the studies, efficacy and safety were similar to those of oral olanzapine, with the exception of an acute adverse effect, the so-called inadvertent intravascular injection event, which occurred 1-3 hours after the injection with an incidence rate of 0.07% per injection. It consisted of symptoms that are similar to those reported in cases of oral olanzapine overdose. The most significant studies published to date, on the use of olanzapine pamoate in schizophrenia, are reviewed in this article. The pharmacodynamic and pharmacokinetic profile and related side effects of OLAI are reported.

Management of refractory complex partial seizures: current state of the art.

Abstract: Diagnosis of complex partial epilepsy is based on the clinical history, and laboratory tests, including EEG and neuroimaging studies, corroborate the diagnosis. The goal of epilepsy management is to make the patient completely seizure-free without drug-induced side effects, even in the patient with refractory complex partial seizures. Frequently this can be accomplished by choice of the optimal antiepileptic drug (AED) or a combination of drugs, the use of strategies to maximize the effectiveness of drug treatment, or by surgical removal of the seizure focus. Currently there are five "classical" first-line AEDs and 11 new AEDs available in the US and in many other countries for the treatment of localization-related epilepsy. The current state of the evidence is that no AED is clearly superior to other AEDs in the management of refractory complex partial seizures. Therefore the choice of which drug to use in an individual patient has to be based on other considerations, including the potential adverse reactions that may occur in that patient. There are a number of strategies for optimal use of AEDs in the management of refractory complex partial seizures. These include verification of the diagnosis of epilepsy and classification of specific seizure types, use of monotherapy if possible but polytherapy if necessary, starting with a low dose and raising it slowly but, until complete seizure control is achieved, pushing to the maximum tolerated dose, changing timing of dosing to reduce toxicity, using pharmacokinetic principles to fine-tune AED doses, adjusting dose for drug-drug interactions, and never giving up in the pursuit of better seizure control. Resection of the seizure focus can be curative in the majority of patients with seizures localized to one mesial temporal lobe. Success rates for resection of extratemporal seizure foci are lower. Vagus nerve stimulation (VNS) devices result in a significant reduction of seizure frequency in many patients, but patients rarely become completely seizure-free as a result of VNS device implantation. Management of refractory complex partial seizures continues to improve with the identification of new drugs and the development of new approaches to their control and cure.