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Biomedical subjects

D Bakish

Publications and source records attributed to D Bakish.

At least 19 recordsLinked to original sources
PubMed2001

Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder.

BACKGROUND: Abnormalities in functioning of the central serotonergic system have been implicated in the pathogenesis of depressive illness and suicidal behavior. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, therefore, it may play an important role in regulation or control of serotonin functions. The aim of the present investigation was to determine whether there is an association between TPH gene polymorphism and major depression. particularly in patients with suicidal ideation. METHODS: A total of 135 unrelated patients suffering from major depressive disorder and 196 normal unrelated controls were included in the study. All controls and patients were Caucasian. A biallelic polymorphism at the tryptophan hydroxylase locus was genotyped. RESULTS: No significant difference between controls and depressed subjects in TPH gene polymorphism was detected. There was no association between TPH gene polymorphism and suicidal ideation. Total HAMD scores were not different between the genotypes or alleles in patients. However, among the HAMD clusters, somatic anxiety was significantly associated with TPH genotypes and alleles in that patients with 218A/A genotype had a significantly higher somatic anxiety scores compared to other genotypes. LIMITATION: Potential confounding effect of population stratification can not be excluded. The functional relevance of the TPH gene 218A/C polymorphism is, at present, uncertain. CONCLUSION: The polymorphism in serotonergic system related genes may be associated with depressive symptoms in major depressive disorder. The results suggest that analysis of clusters that narrow down the phenotype may be more suitable in genetic studies of major depressive illness.

Adult↗
PubMed2001

Serotonergic genes and suicidality.

Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness and suicidal behavior. Studies have shown that the number of brain and platelet serotonin transporter binding sites are reduced in patients with depression and in suicide victims, and that the density of 5-HT2A receptors is increased in brain regions of depressed in suicide victims and in platelets of depressed suicidal patients. Genes that code for proteins, such as tryptophan hydroxylase, 5-HT transporter, and 5-HT2A receptor, involved in regulating serotonergic neurotransmission, have thus been major candidate genes for association studies of suicide and suicidal behavior. Recent studies by our group and by others have shown that genetic variations in the serotonin-system-related genes might be associated with suicidal ideation and completed suicide. We have shown that the 102 C allele in 5-HT2A receptor gene was significantly associated with suicidal ideation (chi2 = 8.5. p < .005) in depressed patients. Patients with a 102 C/C genotype had a significantly higher mean HAMD item #3 score (indication of suicidal ideation) than T/C or T/7 genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression and not with depression itself. We also found that the 5-HT transporter gene S/L polymorphism was significantly associated with completed suicide. The frequency of the L/L genotype in depressed suicide victims was almost double of that found in control group (48.6% vs. 26.2%). The odds ratio for the L allele was 2.1 (95% CI 1.2-3.7). The association between polymorphism in serotonergic genes and suicidality supports the hypothesis that genetic factors can modulate suicide risk by influencing serotonergic activity.

Alleles↗
PubMed2001

New standard of depression treatment: remission and full recovery.

Major depressive disorder (MDD) is a chronic disorder that substantially impairs a patient's psychosocial and occupational functioning. Lifetime prevalence rates for MDD vary widely, ranging from 4.4% to approximately 20%, and it is predicted to become the second leading cause of disability by the year 2020. The magnitude of this public health problem, with its associated decreased quality of life, increased risk of suicide, loss of productivity, and increased health care use, underscores the importance of treating depressed patients to full remission. The presence of residual depressive symptoms due to partial or incomplete remission is associated with significant morbidity and mortality. Hence, complete remission should be the goal in the treatment of patients with MDD because it leads to a symptom-free state and a return to premorbid levels of functioning. Full remission and improved long-term prognosis can be achieved with long-term antidepressant therapy with newer agents that work through multireceptor mechanisms, especially through the serotonergic and noradrenergic systems (i.e., dual action). Robust efficacy and greater remission rates have been associated with dual-action agents.

Acute Disease↗
PubMed2000

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

Adult↗
PubMed2000

Gender differences in association between serotonin transporter gene polymorphism and personality traits.

Since Lesch and colleagues reported an association between anxiety-related traits (Neuroticism) and a functional polymorphism in the serotonin transporter gene regulatory region (5-HTTLPR), there have been several reports on 5-HTTLPR and personality traits with both positive and negative results. The present study was a further attempt to replicate the original findings of Lesch et al. in a population of well-defined normal healthy subjects. In addition, a variable number tandem repeat polymorphism in the second intron was included in this study because it has recently been shown to act as a transcriptional regulator. Personality traits were evaluated in 186 unrelated normal subjects by the NEO Five Factor Inventory. The most important and novel finding of this study was a significant association of mean Neuroticism scores with the short allele of 5-HTTLPR in male subjects (t = 2.4, P = 0.018). We were thus able to replicate the finding of Lesch et al. of an association between serotonin transporter gene polymorphism (5-HTTLPR) and Neuroticism, but only in a male population. We also found a significant effect of gender on mean scores of Neuroticism [F = 3.9, degrees of freedom (df) = 1, 180, P = 0.05] and Agreeableness (F = 6.8, df = 1, 180, P = 0.01), but no significant effect of 5-HTTLPR genotype on Neuroticism (F = 0.87, df= 2, 180, P = 0.42) or Agreeableness (F = 0.35, df = 2, 180, P = 0.7). These findings suggest that gender differences exist in contribution of genetic factors to behavioural phenotypes. They may also explain the inconsistencies in previous reports on association of Neuroticism with 5-HTTLPR from studies using different proportions of male and female subjects.

Adult↗
PubMed2000

An examination of the sensitivity of the six-item Hamilton Rating Scale for Depression in a sample of patients suffering from major depressive disorder.

OBJECTIVES: To compare the sensitivity of the 6-item Hamilton Rating Scale for Depression (HRSD6) with the more widely used 17-item Hamilton Rating Scale for Depression (HRSD17) in patients suffering from major depressive disorder, with or without melancholia and/or dysthymic disorder. A secondary objective was to compare the sensitivity of the HRSD6 to the Montgomery-Asberg Depression Rating Scale (MADRS). DESIGN: Retrospective analysis of 4 clinical trials that tested antidepressant therapies. SETTING: Outpatient treatment in a major psychiatric hospital. PARTICIPANTS: One hundred and forty-three male and female outpatients meeting the criteria of the DSM-III-R or DSM-IV for major depressive disorder. OUTCOME MEASURES: HRSD17, HRSD6 and MADRS. RESULTS: The HRSD6 correlated strongly with the HRSD17, both at baseline and termination of treatment, and for the subgroups of double depression and melancholia. The HRSD6 was also correlated significantly with the MADRS at both measurement times, and for the subgroups. Paired t-tests with the HRSD6, HRSD17 and MADRS demonstrated equal sensitivity to change over the course of treatment, both in the full sample and in the dysthymic and melancholic subgroups. CONCLUSIONS: The HRSD6 appears to be as sensitive to change over treatment as the HRSD17 and the MADRS. A shorter, less time-consuming measure of depression may have utility in clinical practice and research.

Adult↗
PubMed1999

Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression.

The monoamine neurotransmitters serotonin, norepinephrine and dopamine have been implicated in the pathogenesis of depression, schizophrenia and mood disorders. The mechanism of action of certain antidepressant drugs, particularly the tricyclics and the newly available norepinephrine and serotonin reuptake inhibitors (NSRIs) drugs, venlafaxine and nefazodone, suggest that the norepinephrine transporter, which is a target for these antidepressant drugs, and its malfunction may be involved in major depression. In this association study, we tested the hypothesis that variants of the human norepinephrine transporter (NET) gene confer susceptibility to major depression. One hundred and five patients with major depression and 74 unrelated matched controls were analyzed for a silent 1287G/A polymorphism (NET-8) in exon 9 of the NET gene. No significant differences in genotype or allele frequencies were found between controls and patients, nor between subgroups of depressed patients classified by suicidal ideation. In addition, 60 controls and 60 patients were genotyped for a missense substitution Thr99Ile in exon 2 of the NET gene (NET-1), but only one control was heterozygous for this variant. These results suggest that the NET gene is unlikely to be involved in the susceptibility to major depression.

Adult↗
PubMed1999

Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.

BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.

Adult↗
PubMed1999

A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder.

BACKGROUND: Recent studies have suggested clinical differences among selective serotonin reuptake inhibitors. In a 12-week randomized, multicenter, double-blind trial, the antidepressant and anxiolytic efficacy of the selective serotonin reuptake inhibitors paroxetine and fluoxetine was compared in patients with moderate to severe depression. METHODS: A total of 203 patients were randomized to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first six weeks of therapy. From week 7-12, dosing could be adjusted biweekly, as required (paroxetine 20-50 mg/day, and fluoxetine 20-80 mg/day). The mean prescribed doses were paroxetine 25.5 mg/day (range 20.0-40.2 mg/day), and fluoxetine 27.5 mg/day (range 20.0-59.5 mg/day). Emergence of motor nervousness or restlessness was assessed using the ESRS scale for akathisia. RESULTS: Both active treatments demonstrated comparable antidepressant efficacy (HAM-D, CGI). Anxiolytic activity of the two drugs (COVI, STAI, HAM-D) was also comparable. However, paroxetine was found to be superior to fluoxetine on two subscore measures at week 1 of therapy (HAM-D Agitation item, p < 0.05; Psychic Anxiety item, p < 0.05), with no differences detected after week 2. The overall incidence of adverse effects was comparable in the two treatment groups. Constipation, dyspepsia, tremor, sweating and abnormal ejaculation were more common in paroxetine-treated subjects, whereas nausea and nervousness were more frequent in fluoxetine-treated patients. Weight loss was more common in the fluoxetine versus paroxetine group (11.88% versus 2.94%, respectively). ESRS scores for akathisia were low throughout the study and showed little change. LIMITATIONS: Differences observed between the two drugs in antianxiety effects were limited to two measures of anxiety among several others. DISCUSSION: The data indicate that paroxetine and fluoxetine have comparable antidepressant and anxiolytic efficacy. Paroxetine appears to produce an earlier improvement in agitation and psychic anxiety symptoms compared with fluoxetine.

Adult↗
PubMed1999

Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial.

This was an 8-week, multicenter, open-label study of the efficacy and tolerability of venlafaxine in patients with treatment-resistant depression conducted in Canada. Inpatients or outpatients aged 18 to 70 years with major depression were eligible if they had a 21-item Hamilton Rating Scale for Depression (HAM-D-21) score of 2 > or = 18 and a documented history of unsatisfactory improvement after a minimum of 8 weeks of treatment with an adequate dose of an antidepressant. Treatment with venlafaxine was started at 37.5 mg twice daily, and the dose could be titrated upward to a maximum of 375 mg/day during the first 4 weeks on the basis of the investigator's assessment of clinical response and tolerability. Of the 159 patients enrolled, 152 were evaluable for efficacy. The mean daily venlafaxine dose was 260 mg/day. The mean HAM-D-21 score decreased by 52%, and the mean Montgomery-Asberg Depression Rating Scale score decreased by 50% from baseline to day 56. A response (50% improvement from baseline) was achieved by 58% of patients on the HAM-D-21, and a remission (> or = 75% improvement in the HAM-D-21) was observed in 28% at day 56. By day 56, 88% of patients had improved from baseline on the Clinical Global Impression Improvement scale. Only 8% of the patients discontinued for adverse events. The most common adverse events were headache, insomnia, nausea, constipation, diaphoresis, and xerostomia. In conclusion, these results suggest that venlafaxine is effective and well tolerated for the management of patients with treatment-resistant major depression.

Adolescent↗
PubMed1999

The patient with comorbid depression and anxiety: the unmet need.

Major depression and anxiety occur concomitantly in general practice, occur in more patients than either depression or anxiety alone, and are associated with significant morbidity. When depression and anxiety occur together, they are associated with more severe symptoms, increased impairment, a more chronic course and poorer outcome, and a higher incidence of suicide. As many as 80% of patients with generalized anxiety disorder (GAD) have symptoms of depression. Patients with depression and comorbid anxiety present special treatment challenges with selection of drugs that have demonstrated efficacy for both depression and anxiety. A range of effective pharmacotherapeutic strategies are available, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, the 5-HT2 blocker nefazodone, and the serotonin-norepinephrine reuptake inhibitor venlafaxine. Venlafaxine has been extensively evaluated for the treatment of depression and symptoms of anxiety in post hoc analyses. The efficacy of venlafaxine extended release (XR) has been demonstrated in patients with depression and concomitant anxiety. Further, venlafaxine XR is the first antidepressant that has demonstrated significant pure anxiolytic effects in prospective clinical trials of patients with GAD. The spectrum of pure depression, comorbid depression and anxiety disorders, and pure anxiety presents a treatment challenge. Venlafaxine offers a unique pharmacologic approach for the entire spectrum of these disorders.

Antidepressive Agents↗
PubMed1998

A Canadian multicenter study of three fixed doses of controlled-release ipsapirone in outpatients with moderate to severe major depression.

Ipsapirone, an azapirone with 5-hydroxytryptamine (5-HT1A) partial agonist activity, has been shown in preliminary studies to be effective in the treatment of major depressive disorder. This 8-week, randomized, double-blind study compared the efficacy, safety, and tolerability of three fixed doses of controlled-release ipsapirone (10-, 30-, and 50-mg dose once daily) with placebo in 410 patients with moderate to severe major depression (Hamilton Rating Scale for Depression [HAM-D] score > or = 20). The 10-mg ipsapirone treatment arm was discontinued early in the study. A total of 390 patients were eligible for evaluation in the intent-to-treat sample. The primary efficacy variable was the change in HAM-D total score from baseline to visit 8. There was no significant difference in efficacy in the two treatment groups versus the placebo group. The overall treatment response, defined as a 50% decrease in the HAM-D total score from baseline, was 43% with ipsapirone 50 mg given once daily, 34% with ipsapirone 30 mg given once daily, and 35% with placebo. In subanalyses, ipsapirone 50 mg given once daily was superior to placebo according to the HAM-D Core Depression (mood, guilt, interest, psychomotor activity) subtotal (p = 0.0453) and Melancholic item (p = 0.0225). Ipsapirone 30 mg given once daily was superior to placebo only in patients with moderate depression (baseline HAM-D total score < or = 25; p = 0.0100). The most common adverse effect in all groups was headache. The only dose-dependent adverse effects were dizziness and nausea.

Adolescent↗
PubMed1997

Platelet serotonergic indices in major depression: up-regulation of 5-HT2A receptors unchanged by antidepressant treatment.

This study examined, in the largest sample of major depressives reported so far, platelet serotonergic parameters (5-HT uptake, [3H]paroxetine binding and 5-HT2A receptors measured by [3H]LSD binding) in 60 antidepressant-free depressed patients and 40 age- and gender-matched control subjects before treatment, and in 45 major depression patients during treatment with antidepressants. We found that, at baseline, the density (Bmax) of 5-HT2A receptors was significantly higher (by 39%) in depressed patients than in controls. Suicidal patients had significantly higher Bmax values than controls or non-suicidal patients. The rate of serotonin uptake (Vmax), but not the uptake at a single concentration, was significantly higher in depressed patients, particularly in females. There was no significant difference between the Kd or Bmax of [3H]paroxetine binding in control and depressed subjects. Treatment with antidepressant drugs of different pharmacological profile had no significant effect on the density of 5-HT2A receptors, nor did the receptor number predict the response to treatment. The affinity of serotonin uptake site for 5-HT and [3H]paroxetine significantly decreased during treatment with antidepressants, particularly SSRIs. Suppression of 5-HT uptake correlated with decreases in Hamilton depression (HAMD) scores. Our data suggest that the increased density of platelet 5-HT2A receptors may be associated with untreated major depression in antidepressant-free depressed patients, in particular those with suicidal thoughts. The persistence after antidepressant treatment and clinical improvement would suggest that up-regulation of 5-HT2A receptors is a trait rather than state phenomenon. Correlation of 5-HT uptake suppression with decreases in HAMD scores suggests that serotonin uptake inhibition is a relevant factor in antidepressant drug effect and clinical improvement.

Adolescent↗
PubMed1997

Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder.

The effects of treatment with serotonin (5-HT) reuptake inhibitors on platelet 5-HT2 receptors, 5-HT reuptake sites an 5-HT uptake were studied in a double-blind trial comparing two selective serotonin reuptake inhibitors (SSRI), paroxetine, and fluoxetine, for the treatment of major depression. Hamilton Depression Rating Scale (HAM-D) scores and platelet 5-HT parameters were determined in 21 depressed patients at baseline, after 4 and 8 weeks of treatment, and were compared to 21 healthy controls. Antidepressant treatment did not significantly alter the density of 5-HT reuptake sites, labelled with [3H]paroxetine, or 5-HT2 receptors, labelled with [3H]LSD. However, a strong correlation was observed between the HAM-D suicidality item and 5-HT2 receptor density at baseline. A marked increase in platelet 5-HT2 receptors at baseline was observed in suicidal depressed patients compared to those with no suicidal ideation and healthy controls. Changes in [3H]paroxetine Bmax and in [3H]5-HT uptake significantly correlated with change in HAM-D score at 4 and 8 weeks respectively. These results confirm previous reports of an association between suicidality and platelet 5-HT2 receptor upregulation. Our data also lends support to the use of platelet 5-HT parameters as indicators of antidepressant efficacy, particularly in suicidal depressed patients.

Adult↗
PubMed1997

A comparison of patients with major depressive disorder recruited through newspaper advertising versus consultation referrals for clinical drug trials.

Difficulties in recruiting patients for clinical trials have plagued investigators for many years. One concern is the generalizability of clinical trial results to community practice, that is, whether volunteers recruited through advertising are homogeneous with those seeking treatment in a clinical setting. This article retrospectively compares the baseline characteristics of patients recruited through newspaper advertisements with those recruited through consultation referrals by reviewing the charts of 54 patients enrolled in two clinical trials for major depressive disorder (MDD). We examined demographic data, background information, clinical histories, and baseline status. Results indicated homogeneity for most variables. The consultation group was significantly more likely to have had previous treatment for the current episode of depression. These results suggest that, although the advertisement and consultation groups were very similar, the drug naivety of the advertisement group may make them a preferred source in terms of generalizability to community practice.

Adult↗
PubMed1997

Fast onset: an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy.

Pindolol, a beta-adrenergic and presynaptic 5-HT1 vA antagonist, when added to specific serotonin reuptake inhibitors, potentiates the antidepressant action, leading to an earlier onset of effect. Following on from the suggestion that nefazodone, a specific serotonin reuptake inhibitor and antagonist of 5-HT2, improves 5-HT1A-mediated transmission, we used a pindolol and nefazodone combination treatment for major depressive disorder. Twenty outpatients underwent a 4-week trial. Patients were seen twice a week, and completed efficacy and safety measures including the 17-item Hamilton Depression Scale, the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression scales. Results demonstrated significant improvement in all efficacy measures after one visit (2-4 days of treatment), with decreasing depression scores on all measures continuing throughout the trial. After 1 week of treatment, 15 out of 20 patients had experienced a 50% or greater reduction in their 17-item Hamilton Depression Scale scores. Remission rates were dramatic, with 40% of patients in remission after 1 week of treatment and 90% after 4 weeks. This open study of nefazodone-pindolol combination therapy suggests that this may be a new treatment option for patients with major depressive disorder; however, it needs to be replicated in a double-blind trial before conclusions regarding efficacy and safety can be made.

Adrenergic beta-Antagonists↗
PubMed1997

A comparison of placebo response with major depressive disorder in patients recruited through newspaper advertising versus consultation referrals.

Recent evidence indicates few differences between patients recruited through advertising and by consultation referral, and there is some suggestion that those recruited through advertising are more representative of the target community population. However little has been reported on differences in placebo response and compliance in these two patient groups. We conducted a retrospective chart review of 49 patients with major depressive disorder (MDD), recruited through advertising or consultation, randomized to placebo in five clinical trials. Variables included demographics, clinical history, efficacy, compliance, and completion data. Homogeneity was demonstrated for most variables. Differences in placebo groups included significantly lower Hamilton Rating Scale for Depression (HAM-D) scores for the advertisement group throughout the trials. Advertisement patients were also more likely to be early placebo responders and in remission at Days 14 and 28. No differences were found in completion rates or reasons for early termination. Compliance was excellent for both groups. Early placebo response of the advertisement group reinforces the need for trials of at least 8 weeks. In addition, consultation patients may have a more severe illness and be treatment resistant, suggesting they are less generalizable to community practice populations.

Adult↗