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Biomedical subjects

P H Silverstone

Publications and source records attributed to P H Silverstone.

At least 19 recordsLinked to original sources
PubMed2003

Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myoinositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high-resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myoinositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myoinositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI cycle.

Animals↗
PubMed2003

Effects of chronic lithium and sodium valproate on concentrations of brain amino acids.

The present study was designed to determine if the mood stabilizers, lithium and valproate, have common effects on concentrations of amino acid neurotransmitters which may be related to their mechanisms of action. Two separate groups of rats were administered therapeutic doses of lithium, sodium valproate, or saline for 2 weeks. Whole brain extracts were then examined using either high-field 1H NMR spectroscopy or HPLC. Both drugs decreased whole brain concentrations of aspartate, glutamate, and taurine while brain concentrations of gamma-aminobutyric acid (GABA) and alanine decreased following chronic sodium valproate administration but not following chronic lithium administration. These findings indicate that lithium and sodium valproate share common effects on the concentrations of certain amino acid neurotransmitters in whole brain which may be related to their mechanisms of action in bipolar disorder.

Alanine↗
PubMed2002

Two items on the Hamilton Depression rating scale are effective predictors of remission: comparison of selective serotonin reuptake inhibitors with the combined serotonin/norepinephrine reuptake inhibitor, venlafaxine.

Recent studies have shown that the use of subscales derived from the Hamilton Depression (HAM-D) rating scale are just as reliable and enhance sensitivity for detecting response and remission after antidepressant treatment. The purpose of the present study was to determine if the responses on two items of the HAM-D scale, Depressed Mood (item 1) and Psychic Anxiety (item 10), were predictive of remission of depression in placebo-controlled studies following treatment with venlafaxine or selective serotonin reuptake inhibitors (SSRIs). Data from eight active- and placebo-controlled studies consisting of 2027 subjects who met the DSM-III-R/-IV criteria for major depressive disorder were analysed. Three treatment groups were compared: venlafaxine (n =843), SSRI (either fluoxetine, paroxetine or fluvoxamine, n=743) and placebo (n=441). Treatment duration was 6-8 weeks. Patients who scored zero on the depressed mood and the psychic anxiety items of the HAM-D17 scale were designated as responders. These two scores were also combined to create an Absence of Depressive and Anxious Mood (ADAM) score. Between-group rate comparisons in outcome measures were carried out using Fisher's exact test and logistic regression models. Venlafaxine treatment improved depressed mood, psychic anxiety and ADAM scores after 2 weeks with greater efficacy than treatment with SSRIs or placebo. ADAM scores could also predict the odds ratio of a patient achieving a clinical remission (defined as total HAM-D17 score </= 7). The present results demonstrate that using just two items of the HAM-D17 can be very useful in assessing treatment response, differentiating between treatment groups and predicting remission rates.

Adolescent↗
PubMed2001

Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder.

BACKGROUND: A subset of patients with comorbid major depressive disorder and generalized anxiety disorder (GAD) was examined from a double-blind. placebo-controlled study comparing the efficacy and safety of venlafaxine extended release (XR) and fluoxetine. METHOD: From a total of 368 patients, 92 patients meeting DSM-IV criteria for major depressive disorder who also had comorbid GAD were identified. The comparison group comprised 276 evaluable noncomorbid patients. Patients received venlafaxine XR (75-225 mg/day), fluoxetine (20-60 mg/day), or placebo for 12 weeks. Efficacy evaluations included Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions (CGI) scale. RESULTS: By the final assessment at week 12, comorbid patients in the venlafaxine XR group, but not in the fluoxetine group, showed a significantly greater decrease than those in the placebo group in the primary efficacy variables of mean HAM-D and HAM-A total scores (p < .05, pairwise comparison). In comorbid patients, significant pairwise differences were noted between venlafaxine XR and placebo at week 12 for the secondary variables of HAM-D anxiety-somatization and retardation factors, HAM-D depressed mood item. HAM-A psychic anxiety factor, the Hospital Anxiety and Depression scale (HAD) anxiety subscale score, and the Covi Anxiety Scale score. Fluoxetine was significantly different from placebo only on the HAD depression subscale score. Response, defined as > or = 50% decrease in symptoms score, was achieved in 66% and 59% of the comorbid patients for HAM-D and HAM-A, respectively, in the venlafaxine XR group at week 12. This response was higher than that seen with fluoxetine (52% and 45%) or placebo (36% and 24%). Onset of efficacy appeared to be slower in comorbid than in noncomorbid patients. CONCLUSION: This is the first evidence from a controlled study of the effectiveness of pharmacotherapy in patients with comorbid major depressive disorder and GAD. The delayed improvement in comorbid patients compared with noncomorbid patients suggests that a longer treatment period may be necessary in comorbid patients.

Adult↗
PubMed2000

Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI-cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myo-inositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myo-inositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myo-inositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI-cycle.

Animals↗
PubMed2000

Diltiazem as augmentation therapy in patients with treatment-resistant bipolar disorder: a retrospective study.

OBJECTIVE: To examine the efficacy of a slow-release formulation of diltiazem as adjunctive therapy in patients with treatment-resistant bipolar disorder. DESIGN: Retrospective study. PATIENTS: Eight female patients with treatment-resistant bipolar disorder. INTERVENTIONS: Patients were administered diltiazem and monitored for a 6-month period before starting diltiazem and a 6-month period after starting the drug. OUTCOME MEASURES: All patients were seen at least monthly and usually every 2 weeks. The frequency and severity of both depressive and manic episodes were examined during the 6-month period after starting diltiazem, and compared with those during the 6-month period before diltiazem treatment. RESULTS: There was a statistically significant decrease in the frequency and severity of both manic and depressive episodes in these patients after they started treatment with diltiazem, compared with the period before they started treatment with diltiazem (p < 0.001). There was no evidence of side effects requiring patient withdrawal or of drug interactions. CONCLUSIONS: The results support previous suggestions that calcium-channel antagonists may be an effective adjunctive treatment in the management of bipolar disorder. Further controlled clinical studies are needed to confirm this small, open-label, retrospective study.

Antidepressive Agents↗
PubMed1999

Effects of lithium and amphetamine on inositol metabolism in the human brain as measured by 1H and 31P MRS.

BACKGROUND: The clinical effectiveness of lithium may be due to its decreasing the intracellular concentration of myo-inositol and increasing that of its inositol monophosphate precursors, which is known as the inositol depletion hypothesis. METHODS: Magnetic resonance spectroscopy (MRS) was used to measure the concentration of both myo-inositol (1H MRS) and phosphomonoesters (PME) [31P MRS], in healthy volunteers in a double-blind placebo-controlled study. MRS measurements were made at baseline, again on the 7th day of lithium (1200 mg, n = 10) or placebo (n = 6) administration, and again on day 8, 2 hours following oral administration of 20 mg dextroamphetamine to stimulate the phosphoinositol (PI) cycle. RESULTS: Subjects who received lithium showed a greater increase in PME ratios in response to amphetamine administration than did placebo-treated subjects. CONCLUSIONS: The present results support the hypothesis that lithium administration blocks the conversion of inositol monophosphates to myo-inositol, and that this effect is especially apparent following PI cycle stimulation. The effects of lithium treatment on myo-inositol in healthy volunteers in vivo are uncertain, and may have to await improvements in the ability to measure myo-inositol in the brain.

Adolescent↗
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

Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. Venlafaxine XR 360 Study Group.

BACKGROUND: We conducted a randomized, double-blind, placebo-controlled study of the efficacy and safety of once-daily venlafaxine extended release (XR) and fluoxetine in outpatients with major depression and concomitant anxiety. METHOD: Patients who met DSM-IV criteria for major depressive disorder and satisfied eligibility criteria were randomly assigned to once-daily venlafaxine XR, fluoxetine, or placebo for 12 weeks. Efficacy was assessed with the Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions scale. RESULTS: Among 359 outpatients, venlafaxine XR and fluoxetine were significantly superior (p < .05) to placebo on the HAM-D total score beginning at week 2 and continuing to the end of the study. Venlafaxine XR but not fluoxetine was significantly better than placebo at week 2 on the HAM-D depressed mood item. At week 12, the HAM-D response rate was 43% on placebo, 67% on venlafaxine XR, and 62% on fluoxetine (p < .05). The HAM-D remission rate was significantly higher (p < .05) at weeks 3, 4, 6, 8, 12, and final evaluation with venlafaxine XR and at weeks 8, 12, and final evaluation with fluoxetine than with placebo. The HAM-A response rate was significantly higher (p < .05) with venlafaxine XR than with fluoxetine at week 12. The incidence of discontinuation for adverse events was 5% with placebo, 10% with venlafaxine XR, and 7% with fluoxetine. CONCLUSION: Once-daily venlafaxine XR is effective and well tolerated for the treatment of major depression and concomitant anxiety and provides evidence for superiority over fluoxetine.

Adult↗
PubMed1999

Lithium does not alter the choline/creatine ratio in the temporal lobe of human volunteers as measured by proton magnetic resonance spectroscopy.

OBJECTIVE: To study the effect of lithium administration on brain choline/creatine (Cho/Cr) ratios in healthy volunteers. DESIGN: Double-blind, placebo-controlled, prospective study. SETTING: The Nuclear Magnetic Resonance Research Unit at the University of Alberta. PARTICIPANTS: Sixteen healthy volunteers, recruited through advertisements. Subjects were excluded if they had a physical illness, or a personal or family history of psychiatric illness. The study period was from Feb. 6, 1996, to Mar. 21, 1996. INTERVENTIONS: Subjects received a baseline proton magnetic resonance spectroscopy (1H MRS) scan, and then were instructed to take either lithium (1,200 mg) or placebo at night for 7 days. On Day 8, the subjects returned for a second 1H MRS scan. Study participants were seen by a physician at the beginning and at the end of the experiment, and had access to the physician throughout the study period. OUTCOME MEASURES: Ratios of Cho/Cr measured in the temporal lobes by 1H MRS. RESULTS: There were no significant differences in the Cho/Cr ratios between the 2 groups on the test day (placebo 0.748 [standard deviation 0.29] versus lithium 0.811 [SD 0.25]; F = 0.147, p = 0.72), and there was no significant change from baseline in either group (0.003 above baseline for placebo; 0.056 above baseline for lithium; F = 1.21, p = 0.32). CONCLUSIONS: Lithium administration to healthy volunteers does not alter the Cho/Cr ratio in temporal lobe as measured by 1H MRS. The result concurs with reports that differences in Cho/Cr ratios observed in patients with bipolar disorder are likely specific to the illness, and are not the result of lithium therapy. Hence, alterations in choline function are not involved in the clinical effectiveness of lithium.

Adult↗
PubMed1998

Lithium does not attenuate the effects of D-amphetamine in healthy volunteers.

It has previously been suggested that an acute dose of 20 mg D-amphetamine can be a good model of mania. In the present study we attempted to validate this model by determining if subacute administration of lithium (for 7 days) would attenuate the effects of 20 mg D-amphetamine in human volunteers. Sixteen healthy volunteers were enrolled in this double-blind, placebo-controlled study. Subjects received either oral lithium at night for 7 nights (1200 mg) (n = 10) or matching placebo (n = 6). On day 8, subjects were assessed at baseline and then once each hour for 3 h following an oral dose of D-amphetamine (20 mg). Subjective states were measured with visual analog scales, and pulse, systolic and diastolic blood pressure were also repeatedly assessed. The results showed that D-amphetamine alone produced a number of subjective and cardiovascular changes, as expected. However, lithium did not attenuate any of these subjective or cardiovascular changes, as would be predicted if D-amphetamine were a valid model of mania. It is suggested that whilst D-amphetamine may produce effects similar to mania, its mechanism of action is different from that which occurs in mania, and therefore the usefulness of the amphetamine model of mania is called into question.

Adult↗
PubMed1997

Determination of p-trifluoromethylphenol, a metabolite of fluoxetine, in tissues and body fluids using an electron-capture gas chromatographic procedure.

An electron-capture gas chromatographic procedure was developed for the analysis of p-trifluoromethylphenol, an O-dealkylated metabolite of fluoxetine, in biological samples. A basic extraction of the biological sample was employed, followed by derivatization with pentafluorobenzenesulfonyl chloride. The internal standard, 2,4-dichlorophenol, was added to all samples used in the procedure to aid in quantitation. The practical limit of detection (signal-to-noise ratio>3) for p-trifluoromethylphenol was <5 ng/ml in human plasma samples, <10 ng/g of rat brain tissue, <25 ng/g of rat liver tissue and <25 ng/ml in human and rat urine samples. In the rat, the levels of free p-trifluoromethylphenol in the liver were 10-fold higher than those in the brain, and a substantial amount was excreted in the urine. Human urine samples contained levels of free p-trifluoromethylphenol approximately 30-fold higher than those found in human plasma samples. The procedure described is useful for the detection and quantitation of free p-trifluoromethylphenol in humans and rats treated with fluoxetine.

Animals↗
PubMed1997

Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol.

1. Human cytochrome P450 (CYP) isoenzymes expressed in a human cell line were used to elucidate their involvement in the metabolism of haloperidol (HAL). 2. It was found that CYP3A4 catalyzes the metabolism of HAL to HAL 1,2,3,6-tetrahydropyridine (HTP). HTP is further metabolized to HAL pyridinium (HP+) by both CYP3A4 and CYP2D6. 3. CYP3A4 and CYP2D6 are also responsible for the N-dealkylation of HAL. The N-dealkylation of reduced HAL (RH) was observed, which is catalyzed by CYP3A4. In addition, CYP3A4 also catalyzes the oxidation of RH back to HAL. 4. These results are discussed in terms of the metabolic interactions of HAL with other drugs and how this knowledge may be used to reduce the movement disorders induced by HAL.

Biotransformation↗
PubMed1997

Diltiazem, a calcium antagonist, partly attenuates the effects of dextroamphetamine in healthy volunteers.

Calcium antagonists have previously been shown to be effective in the treatment of mania. In the present study we used dextroamphetamine administered to humans as a model of mania, to determine whether the calcium antagonist diltiazem would prevent dextroamphetamine-induced changes. This may help determine whether diltiazem is likely to be useful in the treatment of mania. Ten healthy volunteers were enrolled in this double-blind, placebo-controlled, balanced crossover study. Subjects received either oral diltiazem (60 mg) and placebo, placebo and dextroamphetamine (20 mg), diltiazem and dextroamphetamine, or placebo alone. Subjective and sleep changes were measured using visual analogue scales. Attentiveness and visual reaction times were measured repeatedly as were diastolic and systolic blood pressure. The results showed that dextroamphetamine alone produced a number of subjective changes, cardiovascular changes and changes in reaction time. Diltiazem significantly attenuated the cardiovascular changes, but not the subjective or reaction time changes. It is hypothesized that these findings may represent effects of diltiazem on noradrenergic neurotransmission. The results are tentatively supportive of suggestions that diltiazem may be clinically useful in the treatment of mania, as is another calcium channel antagonist, verapamil.

Adult↗
PubMed1997

The non-antiemetic uses of serotonin 5-HT3 receptor antagonists. Clinical pharmacology and therapeutic applications.

The discovery of multiple subtypes of the serotonin 5-HT receptor has generated enormous interest over the past few years. Possibly the most exciting, in terms of psychiatric clinical practice, appeared to be the 5-HT3 receptor. Early animal studies suggested that the 5-HT3 receptor antagonists, in addition to their well recognised antiemetic use, might be clinically useful in a number of areas. These included anxiety disorders, psychotic disorders, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, the treatment of pain and the treatment of irritable bowel syndrome. With the exception of antiemetic actions, this review examines these potential therapeutic areas carefully, paying particular attention not only to the animal literature, but to the clinical studies which have resulted from these initial findings. Unfortunately, studies in many of these therapeutic areas have not lived up to their initial promise. Indeed, no clinical studies have yet clearly demonstrated the usefulness of 5-HT3 receptor antagonists in the treatment of CNS disorders. Nonetheless, in view of the absence of published results from double-blind, placebo-controlled studies in many of these therapeutic areas, further research would be useful in confirming the effectiveness, or otherwise, of this group of compounds.

Analgesics↗
PubMed1997

A single photon emission computed tomography scan study of striatal dopamine D2 receptor binding with 123I-epidepride in patients with schizophrenia and controls.

The usefulness of 123I-epidepride as a single photon emission computed tomography (SPECT) scan D2 receptor ligand was examined in vivo in 13 medicated patients with schizophrenia and age- and sex-matched normal controls. To establish the effect of endogenous dopamine on 123I-epidepride binding, 4 of the 13 controls also received 20 mg D-amphetamine. The results showed that 123I-epidepride had high specific binding to the striatum in both patients with schizophrenia and normal controls. There was a trend for the total striatal binding of medicated patients with schizophrenia, as measured by total basal ganglia: frontal cortex (TBG:FC) ratios, to be less than the binding of controls (P = 0.053). This trend confirms previous work showing that antipsychotic medication decreases the number of D2 receptors available for binding to the radioligand. Interestingly, there was also a significant relationship between 123I-epidepride binding ratios and global functioning scales (Global Assessment of Functioning scale [GAF]) for schizophrenia (r = 0.56, P = 0.045), although there was no such relationship with the Brief Psychiatric Rating Scale (BPRS). In addition, our results showed that amphetamine-induced dopamine release did not alter 123I-epidepride binding, confirming the high specific binding of 123I-epidepride to the D2 receptor. We conclude that 123I-epidepride appears to be a very useful SPECT ligand for imaging the D2 receptor.

Adult↗
PubMed1997

The foundations of effective management of bipolar disorder.

OBJECTIVES: To understand the epidemiology and course of bipolar disorder; to outline the importance of accurate and reliable diagnosis of bipolar disorder both on a cross-sectional and longitudinal basis; and to emphasize the value of a collaborative therapeutic relationship, psychoeducation, and psychotherapy. METHODS: A brief review of relevant literature to deal with the issues of diagnosis and laying the foundations for effective treatment. RESULTS: Bipolar disorder may well be a heterogeneous group of conditions with varying forms of biphasic mood dysregulation and a changing course across a lifetime. A collaborative therapeutic relationship, psychoeducation, and psychotherapy can be the basis for effective management. CONCLUSIONS: As the concept of bipolar disorder has broadened, the condition is being identified with increasing frequency in many clinical settings. It is a relapsing and recurring condition. It is now recognized that in addition to rational pharmacotherapy, there is a need to encourage a high level of treatment adherence while providing a holistic package of interventions.

Bipolar Disorder↗