Biomedical subjects
Lawrence H Price
Publications and source records attributed to Lawrence H Price.
A case series describing orlistat use in patients on psychotropic medications.
Explore the source record for details and available documents.
Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes.
Fenfluramine releases serotonin (5-HT) via the 5-HT transporter (SERT). Previous work has shown that amphetamine increases particulate protein kinase C (PKC) activity in striatal synaptoneurosomes. The increased PKC activity is linked to the outward transport of dopamine, and when release is diminished, the inward transport of amphetamine inhibits PKC instead. Since there is homology among monoamine transporters, this study was undertaken to determine if D-fenfluramine has similar effects on PKC. The role of 5-HT receptors and endogenous 5-HT were also examined. Naive rats and rats pretreated with p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, were sacrificed. Cortical synaptoneurosomes were prepared and incubated with fenfluramine. PKC activity was determined by thiophosphorylation of endogenous substrates. It was found that 5-HT, D/L-fenfluramine, and D-fenfluramine increased PKC activity in a time- and dose-dependent manner. The 5-HT-mediated increase in PKC activity was attenuated by pretreatment with the 5-HT(2) antagonist ketanserin, but not with the SERT inhibitor fluoxetine. The D-fenfluramine-induced increase in PKC activity was completely prevented, however, by pretreatment with SERT inhibitors and partially with ketanserin. It was also attenuated by pretreatment with PCPA, resulting in a dose-dependent inhibition of PKC instead. Thus, when 5-HT release was diminished the uptake of D-fenfluramine inhibited PKC. Similar effects have been observed with amphetamine. Unlike D-fenfluramine, the D/L-fenfluramine-induced increase in PKC activity was partially resistant to PCPA pretreatment but was attenuated with bupropion, a dopamine transporter (DAT) inhibitor. SERT inhibitors (sertraline, paroxetine, citalopram, and fluoxetine) also increased PKC activity. Nefazodone and bupropion increased PKC activity, but mirtazapine was relatively inactive. The SERT inhibitor-induced increase in PKC was unaffected by pretreatment with PCPA but was inhibited by calcium. Similar effects on PKC activity have been observed with DAT inhibitors. These results, showing that D-fenfluramine altered PKC activity similar to D-amphetamine, suggest that the topographic homology between DAT and SERT may extend to their effects on PKC activity.
Cervical vagus nerve stimulation for treatment-resistant depression.
Therapeutic brain stimulation through left cervical VNS now has established safety and efficacy as a long-term adjunct treatment for medication-resistant epilepsy. There is considerable evidence from both animal and human studies that the vagus nerve carries afferent signals to limbic and higher cortical brain regions, providing a rationale for its possible role in the treatment of psychiatric disorders. Open-label studies in patients with treatment-resistant depression have produced promising results, especially when response rates at longer term (1 year and 2 years) follow-up time points are considered. Short-term (10 weeks) treatment with VNS failed to demonstrate statistical superiority over sham treatment in a recently completed double-blind study, so antidepressant efficacy has not yet been established. Longer term data on VNS in depressed patients as well as further information regarding the possible dose-response relation will help to determine the place of VNS in the armament of therapeutic modalities available for major depression.
Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues.
Intractable OCD and depression cause tremendous suffering in those affected and in their families. The impaired ability to function of those affected imposes a heavy burden on society as a whole. Existing data suggest that lesion procedures offer benefit to a large proportion (ranging from about 35%-70%) of patients with intractable OCD and depression. The literature also suggests that although serious long-term adverse events have occurred, these are relatively infrequent overall. Methodologic limitations of the earlier reports on any of these procedures were described previously in this article. The major academic centers conducting this work have since been obtaining systematic prospective data using modern assessment tools. Nevertheless, even with improved methodologies, more recent studies confront some remaining issues that have been difficult to overcome fully. First, the number of patients who have received any one procedure has been relatively small, constraining statistical power. This limits the ability of researchers to enhance patient selection based on clinical characteristics. This is important, because patients with intractable OCD and depression referred for neurosurgery have high rates of comorbid Axis I diagnoses, personality disorders, and functional impairments, which may have value in predicting response. Other features, such as age of onset, chronicity, and symptom subtypes, may be likewise useful. Another key factor in response may be postoperative management, which has varied most over time but also across patients enrolled in trials. As noted previously, randomized controlled trials of neurosurgical treatment for intractable psychiatric illness have not been reported, although one has been proposed for gamma knife capsulotomy in intractable OCD [23]. The development of deep brain stimulation has also made sham-controlled studies possible and also allows within-patient designs to be considered. Bearing these problems in mind, the literature does provide important guidance on a number of key points, including approaches to referral, patient selection, and the need for long-term prospective follow-up and postoperative management. Nevertheless, important gaps in knowledge remain in all these areas. Research is expected to narrow these gaps in a number of ways, including patient selection, optimizing the procedures themselves, and understanding the mechanisms of therapeutic action. Neuroimaging studies will play a key role in achieving these aims (see the article by Rauch in this issue). So will cross-species translational research on the anatomy and physiology of the pathways implicated in the pathophysiology and response to treatment in these disorders. Future research in psychiatric neurosurgery must proceed cautiously. A recent editorial statement of the OCD-DBS Collaborative Group [26] recommends a minimum set of standards for any multidisciplinary teams contemplating work in this domain. The rationale for those standards is found throughout this issue and is especially developed in the article by Fins. The need for safe and effective therapeutic options for people suffering with these severe illnesses is just as clear. The experience over the last several decades provides grounds for careful optimism that refined lesion procedures or reversible deep brain stimulation may relieve suffering and improve the lives of people with these devastating disorders.
Acute changes in cerebrospinal fluid 5-HIAA following oral paroxetine challenge in healthy humans.
A number of studies have reported decreased human lumbar cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), following chronic administration of selective serotonin reuptake inhibitors (SSRIs). This decrease has been thought to be a consequence of elevated extracellular serotonin and to be mediated through terminal autoreceptor feedback inhibition of serotonin turnover. We wished to study the previously unexamined acute effects of SSRI administration on human CSF 5-HIAA. A serial lumbar puncture (LP) procedure was used to collect CSF samples before and after a single oral 40 mg dose of the SSRI paroxetine (PAR) or matching placebo in eight healthy adult humans in a randomized, double-blind fashion. CSF 5-HIAA concentrations did not change following placebo, but showed a statistically significant 27% mean increase 3 h following PAR. Our findings stand in contrast to the decreases reported for CSF 5-HIAA after chronic SSRI treatment in humans and the decreases seen in brain extracellular 5-HIAA after acute or chronic administration of SSRIs to animals.
Cerebrospinal fluid interleukin-6 in obsessive-compulsive disorder and trichotillomania.
Recent studies have suggested that neuroimmune abnormalities may play an important role in the pathogenesis of obsessive-compulsive disorder (OCD) and related disorders. This study was undertaken to determine whether cerebrospinal fluid (CSF) concentrations of the proinflammatory cytokine interleukin (IL)-6 differ between OCD and trichotillomania patients and healthy control subjects. Lumbar puncture with a standardized procedure was performed on 26 patients with OCD and 9 with trichotillomania. All patients were drug-free and met DSM-IV criteria. Twenty-six age- and sex-matched healthy volunteers underwent the same procedure. CSF was assayed for IL-6 using a quantitative 'sandwich' enzyme immunoassay technique. Mean+/-S.D. CSF IL-6 levels did not differ between OCD patients (n=26) (2.4+/-1.1 pg/ml) and controls (n=26) (2.4+/-1.9 pg/ml) or between trichotillomania patients (n=9) (2.3+/-0.8 pg/ml) and their matched controls (n=14) (1.9+/-0.5 pg/ml). These findings fail to support speculation that ongoing immune activation may be causally involved in the pathogenesis of OCD or trichotillomania.
Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders.
Recently, the addition of drugs with prominent 5-HT(2) receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive-compulsive disorder (OCD). These 5-HT(2) antagonists may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT(2A) receptors. These findings suggest that the simultaneous blockade of 5-HT(2A) receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT(1A) and 5-HT(2C) receptors may counteract the effects of activating 5-HT(2A) receptors. Additional 5-HT receptors, such as the 5-HT(1B/1D/5/7) receptors, may similarly counteract the effects of 5-HT(2A) receptor activation. These clinical and preclinical observations suggest that the combination of highly selective 5-HT(2A) antagonists and SSRIs, as well as strategies to combine high-potency 5-HT(2A) receptor and 5-HT transporter blockade in a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders.
Genotype-controlled analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major depression.
BACKGROUND: Plasma activity of dopamine beta-hydroxylase (DbetaH), the enzyme that converts dopamine to norepinephrine, is reportedly lower in patients with unipolar major depression with psychotic features (UDPF) than in those with nonpsychotic unipolar major depression (UD). Plasma DbetaH is under genetic control by the structural locus encoding DbetaH protein, DBH. This study tested the hypothesis that diagnosis-specific allelic variation at DBH accounts for lower plasma DbetaH in UDPF. METHODS: Plasma DbetaH activity was measured in samples from patients with UDPF (n = 33) and UD (n = 45). Genotypes were determined at several functional DBH polymorphisms, including C-1021T, a single nucleotide polymorphism (SNP) in the proximal 5' region that associates with variation in plasma DbetaH activity. RESULTS: Mean plasma DbetaH activity was significantly lower in UDPF than in UD. Genotyping at DBH did not reveal genetic associations distinguishing UDPF from UD. A two-way analysis of variance showed significant effects of genotype and diagnostic group but no significant interaction. CONCLUSIONS: Although the effects of the diagnosis of UDPF, and of DBH allele status, on plasma DbetaH activity were replicated, the lower plasma DbetaH in patients with UDPF was not accounted for by DBH genotype. Several explanations for this result are possible. First, other variants at DBH, or at other loci, could account for the findings. Second, nongenetic factors could account for the differences in plasma DbetaH. In this regard, we hypothesize that abnormal regulation of hypothalamic-pituitary-adrenal function in UDPF lowers expression of DbetaH protein, which could in turn alter the ratio of dopamine and norepinephrine in noradrenergic neurons, thereby promoting development of psychotic symptoms.
A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine.
BACKGROUND: A previous pilot study of open-label mirtazapine augmentation conducted by the authors in 20 depressed patients yielded a 55% response rate at week 4. A double-blind controlled trial was undertaken to further elucidate the efficacy of this intervention. METHODS: 26 adult outpatients with persistent major depression despite adequate antidepressant monotherapy were randomized to receive 4 weeks of mirtazapine or placebo augmentation. Mirtazapine was begun at 15 mg at bedtime, with possible titration to 30 mg at bedtime per physician's discretion after week 1. RESULTS: Categorical positive response rate at end point was 64% for active drug and 20% for placebo. Remission rates were 45.4% and 13.3% for active drug and placebo groups, respectively, Mirtazapine demonstrated statistically significant superiority to placebo on most major outcome measures, and was associated with improvement in overall functioning and quality of life. There were no significant group differences with regard to emergent side effects, weight change, or serum concentrations of primary antidepressants. CONCLUSIONS: Mirtazapine appears safe and effective for short-term antidepressant augmentation.
A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States.
BACKGROUND: Quantitative trait locus studies, and observations in animals manipulated for the neuropeptide Y (NPY) gene suggest that variation within this gene may contribute to alcoholism. A recent population study suggested that the Pro7 allele of a functional NPY polymorphism (Leu7Pro) may be associated with increased alcohol consumption. We tested whether the Pro7 allele is associated with alcohol dependence in European Americans (EA). METHODS: The design was a population study comparing the Leu7Pro allele frequencies in alcohol-dependent subjects and controls. Population stratification potential and diagnostic specificity was studied by genotyping individuals from additional populations and psychiatric diagnostic classes. We studied 2 independently collected samples of EA alcohol-dependent subjects (sample 1, n = 307; sample 2, n = 160) and a sample of psychiatrically screened EA controls (n = 202); 8 population samples, including African Americans and European Americans (total n = 551); and 4 samples of individuals with Alzheimer disease, schizophrenia, posttraumatic stress disorder, and major depression (total n = 502). The main outcome measure was the difference in Leu7Pro allele frequencies between alcohol-dependent subjects and controls. RESULTS: The frequency of the Pro7 allele was higher in the alcohol-dependent subjects (sample 1, 5.5%; sample 2, 5.0%) compared with the screened EA controls (2.0%) (sample 1 vs controls, P=.006; sample 2 vs controls, P=.03). The attributable fraction (excess morbidity) in similarly affected populations, owing to the Pro7 allele, was estimated to be 7.3%. The frequency of the Pro7 allele was equal or lower in the population samples, as compared with the screened EA controls (0%-2.2%), with 1 exception (Bedouins). We found no significant evidence that the association of the Pro7 allele with alcohol dependence was due to an association with a comorbid psychiatric disorder. CONCLUSIONS: These results suggest that the NPY Pro7 allele is a risk factor for alcohol dependence. This is only the second specific genetic mechanism ever identified that modulates risk for alcohol dependence.
Do obese depressed patients respond to topiramate? A retrospective chart review.
BACKGROUND: Topiramate, a novel anticonvulsant, has shown promise in preliminary open trials in bipolar disorder, but there are no studies in primary depression. Topiramate's tendency to cause weight loss could be advantageous for many patients with mood disorders. METHODS: A chart review was conducted on 16 female outpatients with a primary major depressive episode and mild to moderate obesity who received open-label adjunctive topiramate. Ongoing psychotropics were continued at previous doses. Self-report symptoms were assessed before and after acute phase (4-8 weeks) treatment in a subset of 11 patients, and clinician ratings were assessed at all visits during extended phase (up to 40 weeks) treatment for the entire group. RESULTS: Patient and clinician symptom ratings dropped significantly during acute phase treatment (5.5+/-1.2 weeks), but only 36% of patients were judged responders. At extended phase endpoint (17.7+/-13.4 weeks), 44% of patients were responders. Body mass index decreased significantly on topiramate, reflecting a mean weight loss of 6.1+/-8.2% from baseline. Central nervous system side effects were prominent. CONCLUSIONS: Topiramate may have potential for the adjunctive treatment of depression in obese patients, but close monitoring of weight and adverse effects is warranted.
A retrospective follow-up study of body dysmorphic disorder.
BACKGROUND: Although research on body dysmorphic disorder (BDD) is increasing, no follow-up studies of this disorder's course of illness have been published. METHODS: The status of 95 outpatients with BDD treated in a clinical practice was assessed by chart review. Standard scales were used to rate subjects at baseline and the most recent clinic visit (mean duration of follow-up, 1.7 +/- 1.1; range, 0.5-6.4 years). Ratings were also done at 6-month intervals over the first 4 years of follow-up. RESULTS: Allowing for censoring, life table analysis estimated that the proportion of subjects who achieved full remission from BDD at the 6-month and/or 12-month assessment was 24.7%; the proportion who attained partial or full remission at 6 months and/or 12 months was 57.8%. After 4 years of follow-up, 58.2% had experienced full remission, and 83.8% had experienced partial or full remission, at one or more 6-month assessment points. Of those subjects who attained partial or full remission at one or more assessment points, 28.6% subsequently relapsed. Between baseline and the most recent assessment, BDD severity and functioning significantly improved: at the most recent assessment, 16.7% of subjects were in full remission, 37.8% were in partial remission, and 45.6% met full criteria for BDD. Greater severity of BDD symptoms and the presence of major depression or social phobia at baseline were associated with more severe BDD symptoms at study end point. All subjects received at least one medication trial, and 34.3% received some type of therapy during the follow-up period. CONCLUSIONS: A majority of treated patients with BDD improved, although improvement was usually partial. Prospective longitudinal studies are needed to further elucidate the course of BDD.