Biomedical subjects

S H Kennedy

Publications and source records attributed to S H Kennedy.

At least 19 recordsLinked to original sources

PubMed2005

Placebo-controlled trial of agomelatine in the treatment of major depressive disorder.

The efficacy and safety of flexible dosing with the antidepressant agomelatine (25-50 mg/day) was evaluated in a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for major depressive disorder-current major depressive episode. Patients receiving agomelatine (25 mg and 50 mg/day) had a significantly lower mean Hamilton Rating Scale for Depression (HAM-D) score at endpoint compared with those who received placebo (14.1 +/- 7.7 vs. 16.5 +/- 7.4, p = 0.026). Agomelatine significantly improved the response rate (49.1%; p = 0.03), time to first response (p = 0.032), and Clinical Global Impression-Severity of Illness score (p = 0.017), compared with placebo. These results were confirmed in a subgroup of patients with greater symptom severity. Agomelatine 50 mg also appeared to be effective and well tolerated in patients who failed to show improvement after 2 weeks on a dose of 25 mg/day. These results support the prescription of agomelatine 25 mg as the usual therapeutic dose, and suggest that increasing the dose to 50 mg may be beneficial for some patients without reducing tolerability.

Acetamides↗

PubMed2004

Measurement of the speed of sound in follicular fluid.

BACKGROUND: Measurement of ovarian follicles by ultrasound is common practice in fertility treatment. However, the effect of the speed of sound is not taken into account. We present results from a study aimed at measuring this. METHODS: The speed of sound was measured in samples of follicular fluid aspirated from patients undergoing fertility treatment. The transmitted and received pulses from a single element ultrasound transducer were recorded using a digital oscilloscope for a pulse passed through a sample of the fluid. The distance over which the pulse travelled was known from calibration with pure water. Variation with temperature was investigated in the range 25-45 degrees C. Dependence on ultrasound frequency, patient and time from aspiration were also investigated. RESULTS: The speed of sound in follicular fluid was found to be 1550+/-3 m/s at 37.3 degrees C using 5.0 MHz ultrasound. The speed varied from 1528+/-3 m/s at 24.8 degrees C to 1561+/-3 m/s at 44.8 degrees C. Variation with patient, time and frequency were not detected. CONCLUSION: The speed of sound in follicular fluid at body temperature is 1550 m/s. This small difference from the speed assumed by the ultrasound machine corresponds to the systematic bias in volume measurement evident in previously published results.

Biopsy, Needle↗

PubMed2004

Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder.

There is significant evidence that altered dopamine activity plays a role in seasonal affective disorder (SAD). The current study examined three separate genetic hypotheses for SAD related to the 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), a variant associated with decreased affinity for dopamine. We examined the possible contribution of 7R to the overall expression of SAD, attention deficit disorder (ADD) comorbidity, and body weight regulation. As part of an ongoing genetic study of increased eating behavior and mood in female subjects, 108 women with winter SAD and carbohydrate craving/weight gain were administered the Wender-Utah Rating Scale to measure childhood ADD symptomatology, and a questionnaire to assess maximal lifetime body mass index (BMI). To test for an association between 7R and the categorical diagnosis of SAD, the transmission disequilibrium test (TDT) was used in a subsample of probands providing familial DNA. Standard parametric tests were used to compare childhood ADD symptoms and maximal lifetime BMI across the two genotypic groups defined by the presence or absence of 7R. The TDT found no initial evidence for an association between 7R and the categorical diagnosis of SAD. However, 7R carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. Furthermore, excluding probands with extreme obesity (maximal BMI >40), a strong correlation was found linking childhood inattentive symptoms and maximal lifetime BMI (r=0.35, p=0.001). In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood. This developmental course may reflect different manifestations of the same underlying vulnerability related to central dopamine dysfunction. Given the possibility of population stratification when studying genotype/phenotype relationships, future use of genomic controls and replication of our findings in other overeating and/or ADD populations are needed to confirm these initial results.

Adult↗

PubMed2004

Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study.

The effects of an abrupt interruption of agomelatine, a new melatonergic/serotonergic antidepressant, were explored in a double-blind, placebo-controlled study. Paroxetine was used as active control. After 12 weeks of double-blind treatment with agomelatine 25 mg/day or paroxetine 20 mg/day, sustained remitted depressed patients were randomized for 2 weeks, under double-blind conditions, to placebo or to their initial antidepressant treatment. Discontinuation symptoms were assessed at the end of the first and second week of discontinuation with the Discontinuation Emergent Signs and Symptoms (DESS) checklist. One hundred and ninety-two sustained remitted patients were randomized to the 2-week discontinuation period. Patients who discontinued agomelatine did not experience more discontinuation symptoms than those who continued on agomelatine. Patients who discontinued paroxetine for placebo experienced significantly more DESS discontinuation symptoms, during the first week, compared to those who continued with paroxetine (respective mean number of emergent symptoms: 7.3+/-7.1 and 3.5+/-4.1, P<0.001). No significant difference was shown between the continuing and interrupting groups in the second week of discontinuation. By contrast to paroxetine, abrupt cessation of agomelatine is not associated with discontinuation symptoms.

Acetamides↗

PubMed2003

Recent developments in the psychobiology and pharmacotherapy of depression: optimising existing treatments and novel approaches for the future.

Effective antidepressants include monoamine oxidase inhibitors and tricyclic antidepressants, selective serotonin re-uptake inhibitors and novel agents, including serotonin and noradrenaline re-uptake inhibitors. Although effective, current treatments most often produce partial symptomatic improvement (response) rather than symptom resolution and optimal functioning (remission). While current pharmacotherapies target monoaminergic systems, different symptoms of major depressive disorder (MDD) may have distinct neurobiological underpinnings and other neurobiological systems are likely involved in the pathogenesis of MDD. In this article a review of current pharmacotherapeutic options for MDD, current understanding of the neurobiology and pathogenesis of MDD and a review of new and promising directions in pharmacological research will be provided. It is generally accepted that no single neurotransmitter or system is responsible for the dysregulation found in MDD. While agents that affect monoaminergic systems will likely continue to be first-line treatments for MDD for the foreseeable future, a number of new and novel agents, including corticotropin-releasing factor antagonists, substance P antagonists and antiglucocorticoids show considerable promise for refining treatment options. In order to better understand the neurobiology and treatment response of MDD, it is probable that more sophisticated theory-driven typologies of MDD will have to be developed.

Animals↗

PubMed2002

Polymorphism of the serotonin-2A receptor gene (HTR2A) associated with childhood attention deficit hyperactivity disorder (ADHD) in adult women with seasonal affective disorder.

INTRODUCTION: Several lines of research point to a possible overlap between seasonal affective disorder (SAD) and attention deficit hyperactivity disorder (ADHD), particularly in females. There is also emerging evidence that variation of the 5-HT2A receptor gene (HTR2A) contributes to both SAD and ADHD. The current study investigated whether variation in HTR2A was associated with symptoms of childhood ADHD in adult women with SAD. METHOD: Sixty-six women with SAD were administered the Wender-Utah Rating Scale (WURS), which retrospectively assesses childhood ADHD, as part of an ongoing genetic study of SAD. WURS scores were compared across the three genotypic groups defined by the T102C polymorphism of HT2RA. RESULTS: Analysis of variance indicated a significant difference in mean 25-item WURS scores across the three genotypic groups (p = 0.035). Post-hoc tests revealed that the C/C genotypic group had a significantly higher mean score than both the T/T group and T/C group. Based on previously established WURS criteria, 38% of subjects with the C/C genotype, and none with the T/T genotype, had scores consistent with childhood ADHD. LIMITATIONS: The current sample size is small, and childhood ADHD diagnoses were based on retrospective recall. CONCLUSION: These preliminary results suggest a possible association between variation in HTR2A, childhood ADHD, and the later development of SAD in women.

Adult↗

PubMed2001

Lower dopamine transporter binding potential in striatum during depression.

Previous studies suggest that there is a dopamine lowering process during major depressive episodes (MDE). To investigate this, we measured the dopamine transporter binding potential (DAT BP) in the striatum of depressed and healthy subjects using [(11)C]RTI-32 PET. The DAT, a predominantly presynaptic receptor, decreases in density after chronic dopamine depletion and the BP is proportional to receptor density. In all striatal regions, subjects with MDE had significantly lower DAT BP. Low striatal DAT BP in MDE is consistent with a downregulation of DAT in response to a dopamine lowering process. There was also a strong, highly significant, inverse correlation between striatal DAT BP and neuropsychological tests of dopamine-implicated symptoms in patients (i.e. patients with lower DAT BP performed better). Lower DAT BP itself reduces extracellular clearance of dopamine. Patients who did not decrease their striatal DAT BP failed to compensate for low dopamine and showed greater impairment on dopamine related tests.

Adolescent↗

PubMed2001

Polymorphism of the serotonin 5-HT1B receptor gene (HTR1B) associated with minimum lifetime body mass index in women with bulimia nervosa.

BACKGROUND: Preclinical research has shown that the serotonin-1B receptor has important modulatory effects on feeding behavior and thus body weight. In the current study, we examined whether genetic variation of the serotonin-1B receptor was associated with minimum and maximum lifetime body mass indices (BMIs) in a sample of women with bulimia nervosa (BN). METHODS: Ninety-eight women with BN were genotyped based on the G861C polymorphism of the serotonin-1B receptor gene (HTR1B). Minimum and maximum lifetime BMIs were compared across the three genotypic groups using analysis of variance. RESULTS: There was a highly significant difference in minimum lifetime BMI across the three genotypic groups (p =.001). Both the G/C and C/C genotypes were associated with significantly lower minimum lifetime BMIs than was the G/G genotype. Maximum lifetime BMI was not significantly different across groups. These results were not attributable to different lifetime rates of anorexia nervosa across the three genotypic groups. CONCLUSIONS: These preliminary findings suggest a possible association between HTR1B genetic polymorphism and minimum lifetime BMI in women with BN. These findings may shed light on why, in response to dieting, some BN patients achieve lower BMIs, whereas others have a natural limitation to their weight loss. Pending replication in a larger sample, these findings point to a possible genetic factor of fundamental importance to the BN population.

Adolescent↗

PubMed2001

Toward developing a genome-wide microsatellite marker set for linkage analysis in the rhesus macaque (Macaca mulatta): identification of 76 polymorphic markers.

Linkage analysis can be problematic in humans because of the lack of large, multigenerational pedigrees and the difficulties in obtaining phenotypic data on all family members. In contrast, large, captive colonies of rhesus macaque are a potentially valuable resource for linkage studies because detailed phenotypic and genealogical data are kept, inbreeding is avoided, and DNA samples can usually be obtained. Microsatellite marker sets for genome-wide screening are available in a number of species, but not for the rhesus macaque. We tested primers to 400 human microsatellite markers from a genome-wide mapping set using DNA from nine unrelated female rhesus macaques. We found that 76 (19%) of the primers amplified a polymorphic product using the standard protocols for human DNA. The average heterozygosity of the markers in humans was 0.80, compared to 0.65 in the rhesus macaques. This study provides preliminary data, which could be used toward the development of a linkage mapping set in this species. There would be a need, however, to confirm the Mendelian inheritance of the markers.

Animals↗

PubMed2001

Chronic pelvic pain in the community--symptoms, investigations, and diagnoses.

OBJECTIVES: This study was undertaken to investigate the overlap between chronic pelvic pain, dysmenorrhea, dyspareunia, irritable bowel syndrome, and genitourinary symptoms in the community and also to examine associated investigations and diagnoses. STUDY DESIGN: A postal questionnaire was used to survey 3916 women aged 18 through 49 randomly selected from the Oxfordshire Health Authority Register. The number of responders was 2304 (74% of 3106 questionnaire recipients). Chronic pelvic pain was described as recurrent or constant pelvic pain of > or =6 months' duration unrelated to periods, intercourse, or pregnancy. Case patients (n = 483) were subgrouped as follows: (1) chronic pelvic pain only, (2) chronic pelvic pain and irritable bowel syndrome, (3) chronic pelvic pain and genitourinary symptoms, and (4) chronic pelvic pain, genitourinary symptoms, and irritable bowel syndrome. RESULTS: Half the women with chronic pelvic pain also had either genitourinary symptoms or irritable bowel syndrome, or both. Prevalences of dysmenorrhea and dyspareunia were higher among women with chronic pelvic pain (81% and 41%, respectively) than among women without chronic pelvic pain (58% and 14%, respectively); rates did not differ among the chronic pelvic pain subgroups. Irritable bowel syndrome and stress were the most common diagnoses received by patients with chronic pelvic pain, but 50% had never received a diagnosis. CONCLUSIONS: There is substantial overlap between chronic pelvic pain and other abdominal symptoms in the community. Despite a high prevalence of chronic pelvic pain, many women have never had the condition diagnosed.

Adult↗

PubMed2001

Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTT1 and CYP1A1.

An association between endometriosis and the glutathione S-transferase (GST) M1 null mutation has been reported in French and Slavic populations. We aimed to replicate this association of endometriosis in a UK population, and to test for association with the GSTT1 null mutation or the cytochrome P450 (CYP) 1A1 MspI polymorphism. We genotyped 148 women each with endometriosis (sporadic cases, n = 91; familial cases, n = 57), a population control of 95 male blood donors, and a control group of 53 women with a normal pelvis at hysterectomy. No significant differences were found between cases and controls in the frequencies of the GSTM1 and GSTT1 null mutations, or the CYP1A1 MspI polymorphism. However, the combination of the GSTM1 null genotype and the CYP1A1 MspI polymorphism was associated with a small increased risk of endometriosis, and this warrants further investigation. We also tested for linkage to the chromosome 1p13 region, to which GSTM1 has been mapped, in 52 sister-pairs with stage III-IV disease using three highly polymorphic microsatellite markers. However, there was no evidence of linkage, suggesting that this region may not be implicated in disease susceptibility.

Adult↗

PubMed2001

The genetic basis of endometriosis.

Family studies have long suggested a role for genetic factors in the aetiology of endometriosis. The influence of genes on disease development has mainly been researched independently of environmental factors, yet their interaction must play an important role. Greater exposure to retrograde menstruation and oestrogen is likely to increase the risk of endometriosis; toxic compounds such as dioxin may increase the risk, although the only direct evidence has come from primate studies. Previous association studies implicated GALT (a gene involved in galactose metabolism), and GSTM1 and NAT2 (genes encoding for the detoxification enzymes) as possible disease susceptibility genes. Recent findings have added to the evidence for the involvement of GSTM1 and NAT2, but have cast doubt on the role of GALT. However, the design of many genetic and epidemiological studies has been inadequate with respect to sample size, consistency in phenotype definition, and the choice of control populations. These features are likely to influence results, and could partly explain the lack of consistency in the findings. Future studies should use a consistent disease definition and be of appropriate epidemiological design.

Endometriosis↗

PubMed2001

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

Adolescent↗

PubMed2001

Comparisons of men with full or partial eating disorders, men without eating disorders, and women with eating disorders in the community.

OBJECTIVE: The authors compared 62 men who met all or most of the DSM-III-R criteria for eating disorders with 212 women who had similar eating disorders and 3,769 men who had no eating disorders on a wide variety of clinical and historical variables. METHOD: The groups of subjects were derived from a community epidemiologic survey performed in the province of Ontario that used the World Health Organization's Composite International Diagnostic Interview. RESULTS: Men with eating disorders were very similar to women with eating disorders on most variables. Men with eating disorders showed higher rates of psychiatric comorbidity and more psychosocial morbidity than men without eating disorders. CONCLUSIONS: These results confirm the clinical similarities between men with eating disorders and women with eating disorders. They also reveal that both groups suffer similar psychosocial morbidity. Men with eating disorders show a wide range of differences from men without eating disorders; the extent to which these differences are effects of the illness or possible risk factors for the occurrence of these illnesses in men is not clear.

Adolescent↗

PubMed2001

Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression.

OBJECTIVE: Depression is commonly associated with frontal hypometabolic activity accompanied by hypermetabolism in certain limbic regions. It is unclear whether successful antidepressant treatments reverse these abnormalities or create new resting levels of metabolism. The aim of the present study was to assess the effects of successful paroxetine treatment on regional glucose metabolism in patients with major depression. METHOD: Positron emission tomography with [(18)F]fluorodeoxyglucose was performed on 13 male patients before and after 6 weeks of paroxetine therapy. Resting state scans were also acquired under similar conditions in 24 healthy male subjects for comparison. RESULTS: After successful paroxetine therapy, increased glucose metabolism occurred in dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex (left greater than right), parietal cortex, and dorsal anterior cingulate. Areas of decreased metabolism were noted in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions. In comparison to metabolism levels in a group of healthy volunteers, the increase in prefrontal metabolic activity represented a normalization of previously reduced metabolic activity, whereas the reduction in pregenual anterior cingulate activity represented a decrease from previously elevated metabolic levels. CONCLUSIONS: These results provide further support for a dysfunction in cortical-limbic circuitry in depression, which is at least partly reversed after successful paroxetine treatment.

Adult↗

PubMed2001

Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities.

OBJECTIVE: To review published and nonpublished literature describing changes in weight, glucose homeostasis, and lipid milieu with antipsychotics. METHODS: A Medline search was completed using the words weight gain, diabetes mellitus, cholesterol, triglycerides, risperidone, clozapine, olanzapine, quetiapine, ziprasidone, predictors, prolactin, obesity, and conventional antipsychotics. Publications, including original articles, review articles, letters to the editor, abstracts or posters presented at professional meetings in the last 4 years, and references from published articles, were collected. Manufacturers, including Eli Lilly Canada Inc, JanssenOrtho Inc, Pfizer Canada Inc, AstraZeneca Inc, and Novartis Pharmaceuticals, were contacted to retrieve additional medical information. RESULTS: The topic of antipsychotic-induced weight gain is understudied, and there are relatively few well-controlled studies. Weight gain as a side effect has been described with both conventional and atypical antipsychotics. Moreover, some atypical antipsychotics are associated with de novo diabetes mellitus and increased serum triglyceride levels. Predictors of weight gain may be age, baseline body mass index, appetite stimulation, previous antipsychotic exposure, and antipsychotic treatment duration. CONCLUSION: Significant weight gain is reported with the existing atypical antipsychotics. The weight gain described is highly distressing to patients, may reduce treatment adherence, and may increase the relative risk for diabetes mellitus and hypertriglyceridemia. Physicians employing these agents should routinely monitor weight, fasting blood glucose, and lipid profiles.

Adult↗

PubMed2001

Lithium revisited.

OBJECTIVE: To review lithium's utility in the treatment of mood disorders. METHOD: We reviewed the safety, tolerability, teratogenicity, optimal dosing regimens, and mortality-lowering effects of lithium. Clinical relevance and scientific rigour determined which articles we selected for review. RESULTS: Lithium is the paradigmatic treatment for bipolar disorder (BD). In treating BD, optimal maintenance plasma levels may be approximately 0.75 to 0.85 mEq/L. Although nephrogenic diabetes insipidus is not uncommon, irreversible renal failure due to lithium appears to be a rare, idiosyncratic event. Lithium-induced cardiovascular teratology appears to be less common than previously thought. Optimal lithium dosing may be once daily, this agent appears to bestow a robust suicide-lowering effect, and emerging data hint at neurotrophic and neuroprotective effects. CONCLUSION: Lithium remains an effective and integral agent in the treatment of BD. Its ability to lower suicide rates in persons with BD warrants clinical attention.

Adverse Drug Reaction Reporting Systems↗

PubMed2001

Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments.

BACKGROUND: The Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments partnered to produce clinical guidelines for psychiatrists for the treatment of depressive disorders. METHODS: A standard guidelines development process was followed. Relevant literature was identified using a computerized Medline search supplemented by review of bibliographies. Operational criteria were used to rate the quality of scientific evidence, and the line of treatment recommendations included consensus clinical opinion. This section, "Medications and Other Biological Treatments," is 1 of 7 articles that were drafted and reviewed by clinicians. Revised drafts underwent national and international expert peer review. RESULTS: Evidence-based recommendations are presented for 1) choosing an antidepressant, based on efficacy, tolerability, and safety; 2) the optimal use of antidepressants, including augmentation, combination, and switching strategies; 3) maintenance treatment; and 4) electroconvulsive therapy (ECT), light therapy, and additional somatic treatments. Evidence from metaanalyses is presented first, followed by conclusions from randomized controlled trials (RCTs) and, if appropriate, open-label data. CONCLUSIONS: There is significant evidence to support the role of selective serotonin reuptake inhibitors (SSRIs), novel agents, and classic agents in the treatment of major depressive disorder (MDD). There is also evidence to support the use of somatic treatments, including ECT and light therapy, for some patients with MDD. There is limited evidence for the use of specific medications to treat subtypes of MDD. There is emerging evidence to support augmentation and combination strategies for patients previously nonresponsive to medication.

Algorithms↗