Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ( approximately 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.     

A meta-analysis of fluoxetine outcome in the treatment of depression

A meta-analysis was conducted on all the double-blind, placebo-controlled efficacy trials of the antidepressant fluoxetine (Prozac). This drug has become the antidepressant most frequently prescribed by psychiatrists and has been hailed by the media as a "wonder drug." Results produced a relatively modest overall effect size that was no greater than effect sizes obtained by previous meta-analyses of tricyclic antidepressants. This study also examined the possibility that bias may have contaminated study outcome ratings. Because past studies suggest that the greater frequency of side effects in active drug groups unblinds study participants, we examined the relationship between study effect sizes and the percentage of patients reporting side effects. As predicted, both clinician and patient outcome ratings correlated significantly with the percentage of patients experiencing side effects. Questions are raised about the role of side effects in mediating drug outcome results.     

A double-blind study of paroxetine, fluoxetine, and placebo in outpatients with major depression

Human milk has a higher concentration of nucleotides than bovine milk which is the source of most infant formulas. As the composition of human milk is considered the 'gold standard,' an increasing number of infant formulas are supplemented with nucleotides. This review summarises the biology of human milk nucleotides and evaluates the studies which investigated the clinical benefits of feeding infants with nucleotide-supplemented formulas. Although dietary nucleotides have been suggested to have beneficial gastrointestinal and immunological effects, nucleotide-supplemented formula feeding has not been shown to confer the same benefits as breast feeding, and randomised controlled trials have yet to prove that healthy term infants fed nucleotide-supplemented formulas compared to those fed nonsupplemented formulas, have accelerated physical growth and neurological development, better growth and development of their gastrointestinal tract resulting in improved digestive and absorptive functions, enhanced development of their immune system resulting in increased resistance to infection and lower bacterial and viral infection rates during infancy, and a more favourable intestinal microflora associated with a lower rate of infectious diarrhoea. However, a randomised controlled trial has reported that term infants with severe intrauterine growth retardation do have better catch-up growth with nucleotide supplementation. The hypothesis that nucleotides are semi-essential nutrients needs to be further studied, in particular in the presence of prematurity, fetal growth retardation, intestinal injury and limited nutrient intake. As no deleterious effects have been reported with the use of nucleotide-supplemented formulas, the first of which was introduced over 30 years ago, such products are considered safe when nucleotides are supplemented to an amount equivalent to the free nucleotide concentration of human milk. More basic and clinical research studies are awaited to further define the biology and role of human milk nucleotides, and to critically assess the potential benefits and appropriate level of nucleotide supplementation of infant formula.     

A double-blind, randomized, fixed-dose trial of fluoxetine vs. amitriptyline in the treatment of major depression complicating Alzheimer''s disease

Serum-soluble HLA class I molecules (sHLA) have immunomodulatory functions and their serum levels correlate with the HLA class I phenotype. We studied longitudinal changes of serum sHLA levels in insulin-dependent diabetes mellitus (IDDM). A total of 198 serum samples were obtained from 40 IDDM patients before and after IDDM onset. sHLA was assayed by a sandwich ELISA. sHLA levels in IDDM patients at the initiation of insulin therapy (IDDM onset) were markedly reduced compared with those in normal controls (334.2 +/- 26.3 ng/ml vs 492.4 +/- 55.5 ng/ml, mean +/- SEM, P = 0.0038). They fell sharply during 6 months before and after the onset of IDDM. The dynamic profile of sHLA and the time course of beta-cell loss were different between IDDM patients with and without HLA-A24. In those with HLA-A24, sHLA became significantly lower than normal controls with HLA-A24 at IDDM onset. Recovery of their sHLA values occurred at 3 years from IDDM onset. On the other hand, in those without HLA-A24, sHLA levels began to decrease since the onset of IDDM and became significantly lower than normal controls without HLA-A24 at 4 years after the onset. Recovery of sHLA occurred at more than 6 years from the onset. An early (within 18 months), complete loss of beta-cell function occurred in 5 of 13 IDDM patients with HLA-A24 compared with 1 of 14 of those without HLA-A24 (P = 0.077). A late (more than 36 months after the onset of IDDM), complete loss of beta-cell function occurred in 7 of 14 IDDM patients without HLA-A24 but in none of 13 of those with HLA-A24 (P = 0.0058). These results indicate that the decline of sHLA is synchronous with massive beta-cell destruction, and that these events occur during a short period in IDDM patients with HLA-A24, whereas they occur during a relatively long period in those without HLA-A24.     

Dichotic listening before and after fluoxetine treatment for major depression: relations of laterality to therapeutic response

A policy capturing method combining human judgment with ridge regression is offered which results in superior judgment policy models. The new method (termed smart ridge regression) was tested against four others in seven judgment policy capturing applications. Performance criteria were two cross-validation indices: cross-validated multiple correlation and mean squared error of prediction of new judgments. Smart ridge regression was found to outperform ordinary least squares regression and conventional ridge regression, as well as subjective weighting and equal weighting of cues.     

Expenditures for the treatment of major depression

At present, little information is available on specific chromosomal aberrations in malignant melanomas of different subtypes and different growth behaviors. Therefore, we have applied fluorescence in situ hybridization on isolated interphase cells from paraffin sections of 79 primary tumors of malignant melanomas: 47 nodular melanomas and 32 superficial spreading melanomas in various stages. We used centromeric probes for the chromosomes 1, 4, 6, 7, 9, 10, 11, 12, 15, 17, 18, X, and Y and a midisatellite probe localized in 1p36. The number of chromosomal aberrations and the ploidy of the cells rose with the tumor stage in both subtypes, although in superficial spreading melanomas, fewer chromosomal abnormalities were detectable than in nodular melanomas. A deletion in 1p36 could only be found in nodular melanomas (mostly in higher tumor stages), not in superficial spreading melanomas. Our results show that the different histologic subtypes of malignant melanoma of the skin differ also in their chromosomal aberrations. In addition, it seems that there may be a correlation between the growth characteristics and putative tumor suppressor genes on 1p36.     

A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression

OBJECTIVE: To determine amitriptyline's (AMI) efficacy in the acute treatment of adolescent major depressive disorder (MDD). METHOD: Subjects aged 12 through 17 years meeting Research Diagnostic Criteria for MDD, diagnosed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS), participated in a 2-week placebo-washout followed by an 8-week, randomized, double-blind, parallel-design, placebo-controlled trial of AMI, 5 mg/kg per day. The K-SADS nine-item scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions rating scale were used as outcome measures. RESULTS: Thirty-one subjects were randomized (18 AMI, 13 placebo). Twenty-two subjects were study completers (12 AMI, 10 placebo). AMI's efficacy was suggested by the Clinical Global Impressions but not the K-SADS-derived data. Perhaps the primary limitation of the current study is its small sample size. CONCLUSION: No definitive recommendation can be made regarding the efficacy of tricyclic antidepressants in the treatment of adolescent MDD.     

Long-term treatment of psychotic (delusional) depression with fluvoxamine: an open pilot study

The aim of this open pilot study was to evaluate the efficacy of fluvoxamine in the continuation as well as in the maintenance therapy of delusional depression. Thirty patients with recurrent, unipolar depression (DSM-IV criteria) were selected who had at least one depressive episode during the 18 months preceding the delusional depressive index episode and were treated with fluvoxamine 300 mg/day. Twenty-five of them had a sustained response to this short-term treatment and agreed to enter into the 30-month follow up study. All participants completed the follow up period. No relapse was observed during the 6 months of continuation therapy. During the further 24 months of maintenance therapy, 80% of the patients remained well, whereas 20% (five out of 25) had a single recurrence. Based on these observations, fluvoxamine might be a promising drug for long-term therapy of delusional depression. Further controlled studies are required to confirm this finding.     

A comparison of cognitive-behavioral therapy and relaxation training for the treatment of depression in adolescents.

30 moderately depressed high school students were randomly assigned to either cognitive-behavioral treatment, relaxation training, or a wait-list control condition. Treatment Ss met in small groups for 10 50-min sessions over 5 wks in a high school setting. Outcome measures included a modified Beck Depression Inventory, the Rosenberg Self-Esteem Scale, and the State-Trait Anxiety Inventory. The cognitive-behavioral and relaxation training groups were superior to the wait-list control group in the reduction of depressive symptoms at both posttest and 5-wk follow-up assessments. There was no significant difference between active treatments in their effectiveness for reducing depression. Ss in the cognitive-behavioral and relaxation training conditions went from moderate levels of depression at pretest to nondepressed levels at posttest, and they maintained these levels at follow-up. Improvements in anxiety and academic self-concept were also demonstrated by the active treatments. Findings demonstrate that these short-term group-administered therapies are effective in significantly decreasing depression in adolescents. (48 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A double-blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed inpatients

External root resorption is one of the most exasperating and least understood clinical problems in orthodontics. Numerous studies have been conducted, attempting to establish the factors causing root resorption of permanent teeth. Considerable variation exists however, in the extent and distribution of root resorption, seen in the orthodontic treatment of apparently similar cases. After an excellent review of the literature, Brezniak and Wassertein (1993) concluded that the most significant disgnostic aid in predicting whether root resorption would occur during orthodontic treatment, is the radiographic evidence of root resorption before treatment. A case is reported, describing the dilemma of orthodontically treating a patient, who had previously experienced trauma to the upper right central incisor, leading to external root resorption.     

A comparison of cognitive and interpersonal-process group therapies in the treatment of depression among college students.

We compared cognitive (CT) and interpersonal-process (IP) group therapies in the treatment of moderate, unipolar depression in college counseling-center clients. Subjects who sought services early in the semester were randomly assigned to CT or IP groups and compared with a waiting-list group composed of subjects who requested services just prior to the Christmas recess. Multivariate analyses revealed no significant differences between treatment and waiting-list conditions. Because the control was confounded by the Christmas holiday, we compared the CT and IP groups directly. Both treatments led to significant reductions in depression and depressed thinking and to increments in self-esteem at midtreatment, posttreatment, and follow-up assessments but did not differ from each other at any other time. There was no evidence of differential effectiveness or mechanisms of therapeutic change as a function of type of treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A double-blind comparison of the efficacy and safely of paroxetine and imipramine in the treatment of depression with dementia

Marrow stromal cells of patients treated by autologous bone marrow transplantation (ABMT) for malignancies have been assessed for their ability to secrete granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), transforming growth factor beta1 (TGFbeta1) and macrophage inflammatory protein-1alpha. (MIP-1alpha). Long-term marrow cultures were established from 10 patients prior to and 3 months after ABMT, from 7 patients 1 yr after ABMT and from 11 controls. Cytokines in culture supernatants of stromal layers (SL) were evaluated by enzyme-linked immunosorbent assay (ELISA). Significant differences between patient groups and controls were apparent in baseline production of GM-CSF, SCF, MIP-1alpha and TGFbeta1. After IL-1beta addition in cultures, G-CSF production was reduced in pretransplant and post-transplant patients compared to controls. The production of TGFbeta1, LIF, IL-6 and more particularly SCF were reduced in post-transplant patients, while elevated levels of GM-CSF and MIP-1alpha were observed in these patients only when the values were corrected for the number of cells growing in the SL. These results indicate a prolonged stromal defect in growth factor production following ABMT for the early-stage acting cytokines IL-6, LIF and SCF as well as for G-CSF, but not for GM-CSF, while the production of the 2 inhibitors shows different pathways.     

A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression

BACKGROUND: Depression is a major cause of morbidity and mortality in children and adolescents. To date, randomized, controlled, double-blind trials of antidepressants (largely tricyclic agents) have yet to reveal that any antidepressant is more effective than placebo. This article is of a randomized, double-blind, placebo-controlled trial of fluoxetine in children and adolescents with depression. METHODS: Ninety-six child and adolescent outpatients (aged 7-17 years) with nonpsychotic major depressive disorder were randomized (stratified for age and sex) to 20 mg of fluoxetine or placebo and seen weekly for 8 consecutive weeks. Randomization was preceded by 3 evaluation visits that included structured diagnostic interviews during 2 weeks, followed 1 week later by a 1-week, single-blind placebo run-in. Primary outcome measurements were the global improvement of the Clinical Global Impressions scale and the Children's Depression Rating Scale--Revised, a measure of the severity depressive symptoms. RESULTS: Of the 96 patients, 48 were randomized to fluoxetine treatment and 48 to placebo. Using the intent to treat sample, 27 (56%) of those receiving fluoxetine and 16 (33%) receiving placebo were rated "much" or "very much" improved on the Clinical Global Impressions scale at study exit (chi 2 = 5.1, df = 1, P = .02). Significant differences were also noted in weekly ratings of the Children's Depression Rating Scale--Revised after 5 weeks of treatment (using last observation carried forward). Equivalent response rates were found for patients aged 12 years and younger (n = 48) and those aged 13 years and older (n = 48). However, complete symptom remission (Children's Depression Rating Scale--Revised < or = 28) occurred in only 31% of the fluoxetine-treated patients and 23% of the placebo patients. CONCLUSION: Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression. Complete remission of symptoms was rare.     

Delirium during fluoxetine treatment. A case report

The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased somnolence and movement difficulties. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus desmethylfluoxetine) concentration.     

Contingency management treatment of outpatient unipolar depression: A comparison of reinforcement and extinction.

This study examined the differential effects of reinforcement versus extinction in contingency management of outpatient unipolar depression for 6 depressed subjects and their significant others. We used an alternating-treatments design (with a multiple baseline across subjects) to provide subjects with 4 weeks of reinforcement for a targeted deficit and 4 weeks of extinction for a targeted excess. The results (a) confirmed the efficacy of contingency management, administered by significant others, for outpatient unipolar depression; (b) demonstrated the predicted behavior change and decreased depression for both reinforcement and extinction; and (c) showed that responses covaried in an individualistic manner across subjects and varied across reinforcement and extinction. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Personality, stressful life events, and treatment response in major depression.

The current study examined whether the personality traits of self-criticism or dependency moderated the effect of stressful life events on treatment response. Depressed outpatients (N = 113) were randomized to 16 weeks of cognitive–behavioral therapy, interpersonal psychotherapy, or antidepressant medication (ADM). Stressful life events were assessed with the Bedford College Life Events and Difficulties Schedule. Severe events reported during or immediately prior to treatment predicted poor response in the ADM condition but not in the psychotherapy conditions. In contrast, nonsevere life events experienced prior to onset predicted superior response to treatment. Further, self-criticism moderated the relation of severe life events to outcome across conditions, such that in the presence of severe stress those high in self-criticism were less likely to respond to treatment than were those low in self-criticism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)