Homeopathic Individualized Q-Potencies versus Fluoxetine for Moderate to Severe Depression: Double-Blind, Randomized Non-Inferiority Trial.

Homeopathy is a complementary and integrative medicine used in depression, The aim of this study is to investigate the non-inferiority and tolerability of individualized homeopathic medicines [Quinquagintamillesmial (Q-potencies)] in acute depression, using fluoxetine as active control. Ninety-one outpatients with moderate to severe depression were assigned to receive an individualized homeopathic medicine or fluoxetine 20 mg day(-1) (up to 40 mg day(-1)) in a prospective, randomized, double-blind double-dummy 8-week, single-center trial. Primary efficacy measure was the analysis of the mean change in the Montgomery & Åsberg Depression Rating Scale (MADRS) depression scores, using a non-inferiority test with margin of 1.45. Secondary efficacy outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society of Psychopharmacology. Mean MADRS scores differences were not significant at the 4th (P = .654) and 8th weeks (P = .965) of treatment. Non-inferiority of homeopathy was indicated because the upper limit of the confidence interval (CI) for mean difference in MADRS change was less than the non-inferiority margin: mean differences (homeopathy-fluoxetine) were -3.04 (95% CI -6.95, 0.86) and -2.4 (95% CI -6.05, 0.77) at 4th and 8th week, respectively. There were no significant differences between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between the side effects rates, although a higher percentage of patients treated with fluoxetine reported troublesome side effects and there was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. This study illustrates the feasibility of randomized controlled double-blind trials of homeopathy in depression and indicates the non-inferiority of individualized homeopathic Q-potencies as compared to fluoxetine in acute treatment of outpatients with moderate to severe depression.

Family interventions for bipolar disorder.

BACKGROUND: Pharmacological treatments are the principal intervention for bipolar disorder. Alone, however, they are not sufficient to control symptoms and maintain psychosocial functioning. Adjunctive psychosocial interventions may help to improve the patient's condition and the course of the illness. Family interventions are deserving of special attention, since they may help to relieve the burden of care borne by relatives and caregivers, which in turn may facilitate the task of supporting the patient. OBJECTIVES: The objective of this review was to investigate the effectiveness of family interventions in the treatment of bipolar disorder compared with no intervention and other forms of intervention. SEARCH STRATEGY: We searched the electronic databases CCDANRCT-Studies and CCDANCTR-References on 1/8/2007, CENTRAL (2006-3), MEDLINE (2006), EMBASE (2006) and LILACS (2006), and searched the reference lists of included studies. We also made personal contact with authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised trials. Participants were people with bipolar disorder and their relatives or caregivers; family psychosocial interventions of any type were considered; primary outcomes were changes in the status of symptoms and relapse rates. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two review authors. Quality assessment of included studies was carried out. The findings were presented descriptively. Where there were sufficient studies, dichotomous data were combined using relative risk, and continuous data were combined using weighted mean difference, with their 95% CIs. MAIN RESULTS: Seven RCTs were included in the review, involving a total of 393 participants. All of the included studies assessed psychoeducational methods, and one study also assessed a type of systems psychotherapy. In all trials, participants continued to receive pharmacotherapy treatment. Due to the diversity of interventions, outcome measures and endpoints used across studies, it was not possible to perform meta-analyses for primary outcomes. Five studies compared a variety of family interventions, involving carers, families or spouses, against no intervention, with individual findings indicating no significant added effect for family interventions. Three studies compared one type or modality of family intervention against another family intervention, with inconsistent findings. AUTHORS' CONCLUSIONS: To date there is only a small and heterogeneous body of evidence on the effectiveness of family oriented approaches for bipolar disorder, and it is not yet possible to draw any definite conclusions to support their use as an adjunctive treatment for bipolar disorder. Further well designed RCTs should be a research priority.

Alteration of norepinephrine metabolism with desipramine and zimelidine in depressed patients.

Twelve patients with a major affective disorder were treated during the depressed phase of their illness with desipramine hydrochloride and/or zimelidine hydrochloride, and urinary excretion rates of norepinephrine and its major metabolites were examined. During treatment with desipramine, daily urinary excretion of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid was reduced, but urinary normetanephrine excretion was not significantly changed. In all patients, the proportion of urinary norepinephrine metabolites represented by normetanephrine was increased during desipramine treatment. Independent of treatment outcome, desipramine seemed to decrease total formation and metabolism of norepinephrine, which was reflected in decreases in the excretion rate of the catecholamine and its metabolites. These results are consistent with known actions of desipramine on the disposition of norepinephrine and represent alterations in the rate of norepinephrine formation and metabolism, resulting from inhibition of norepinephrine reuptake. Zimelidine, a new antidepressant, which is a relatively specific serotonin-uptake inhibitor, significantly reduced only urinary MHPG excretion without appearing to alter "whole-body" norepinephrine turnover. This effect of zimelidine on norepinephrine metabolism was unexpected. Current and previous findings concerning clorgyline, a relatively specific monoamine oxidase A inhibitor, suggest that three pharmacologically distinct classes of antidepressants, norepinephrine and serotonin-reuptake and monoamine oxidase type A inhibitors, all reduce central norepinephrine turnover in depressed patients.

WHO Neuropsychiatric AIDS study, cross-sectional phase I. Study design and psychiatric findings.

BACKGROUND: Most available studies on the psychiatric, neuropsychological, and neurological complications of HIV-1 infection and AIDS have been conducted in Western countries, on samples of well-educated, mostly white, homosexual men. Concerns about generalizability of the results of those investigations prompted the WHO to implement the cross-cultural venture called WHO Neuropsychiatric AIDS study. METHODS: This project aims to assess the prevalence and natural history of HIV-1-associated psychiatric, neuropsychological, and neurological abnormalities in representative subject samples enrolled in the five geographic areas predominantly affected by the HIV-1 epidemic. Assessment is made by a data collection instrument including six modules. The intercenter and intracenter reliability in the use of each module has been formally evaluated. The study consists of a cross-sectional phase and a longitudinal follow-up. RESULTS: The cross-sectional phase was completed in five centers. This paper reports on the results of psychiatric assessment, which revealed a significantly higher prevalence of current mental disorders in symptomatic seropositive persons compared with seronegative controls among intravenous drug users in Bangkok and homosexuals/bisexuals in São Paulo. The mean global score on the Montgomery-Asberg Depression Rating Scale was significantly higher in symptomatic seropositive individuals than in matched seronegative controls in all centers. CONCLUSIONS: These results suggest that the significance of the psychopathological complications of symptomatic HIV-1 infection may have been underestimated by previous studies conducted on self-selected samples of well-educated, middle-class, mostly white, homosexual men.

Selective antidepressants and cerebrospinal fluid. Lack of specificity on norepinephrine and serotonin metabolites.

Cerebrospinal fluid concentrations of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid, were measured in depressed patients before and after treatment with three putatively specific antidepressants. The expected specificity of action on these three neurotransmitter metabolites was not observed. Desipramine hydrochloride, a norepinephrine uptake inhibitor, reduced 5-HIAA as well as MHPG concentrations; zimeldine hydrochloride, a serotonin uptake inhibitor, reduced MHPG as well as 5-HIAA concentrations; and clorgyline, a selective monoamine oxidase type A inhibitor, which might be predicted to most affect 5-HIAA, dramatically reduced MHPG, moderately reduced homovanillic acid, and only modestly reduced 5-HIAA concentrations.

The effects of lithium carbonate on healthy volunteers: mood stabilization?

A 2-month lithium-placebo double-blind cross-over study was carried out with 17 healthy volunteers. Their mood was self-rated: twice daily (AM, PM) with the Visual Analogue Mood Scale (VAMS); weekly with the analogue scales for subjective states and body symptoms; and three times (basal and at the end of each treatment period) with the Profile of Mood States (POMS). Memory and reaction time were also assessed, but did not show any change. The mean VAMS score decreased during lithium treatment, but the mean mood variability, a measure of the mean successive differences between consecutive mood ratings (delta squared), did not change significantly. There was a tendency toward decreased mood variability on lithium, both during the full 1-month treatment period and in the last week of treatment, when all volunteers had a lithium serum level ranging from 0.6 to 1.0 mEq/liter. The lower mean VAMS scores on lithium could be attributed to lithium-induced dysphoric mood as recorded on the analogue scales and POMS. However, very large inter- and intraindividual differences in response to lithium were observed. Actually, lithium even had an opposite effect on some volunteers' mood. The data and problems involved with assessment of mood and its changes are discussed.

Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity.

Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of these drugs. The present study shows that the hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine, and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as do their parent compounds. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. Following chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the cerebrospinal fluid. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help to clarify whether there is a relationship between active drug concentration and clinical effect.

Zimelidine and norzimelidine protein binding measured by equilibrium dialysis and cerebrospinal fluid.

Steady-state concentrations of a new antidepressant, zimelidine (ZIM), and its active metabolite, norzimelidine (NZIM), were measured in plasma and cerebrospinal fluid (CSF) in eight depressed patients. Free drug, as calculated from the ratio of CSF to plasma concentration, of ZIM was 8.4 +/- 1.8% and of NZIM was 18.3 +/- 2.8%. Equilibrium dialysis (ED) of plasma from the same patients on placebo yielded free fractions of 8.6 +/- 2.2% and 28.1 +/- 3.4% for the two compounds. alpha 1-Acid glycoprotein (alpha a-AG) was also measured in the same samples. Variation in free drug using either method was not great, but did modestly correlate with alpha 1-AG concentration in six of the eight patients in whom simultaneous placebo measures were available. Our results indicate that measurements in plasma or of free drug dependent on ED lead to erroneous conclusions regarding the proportion of free NZIM to ZIM. Considering the different potencies of the parent compound and active metabolite, this is an unusual problem.

Effects of desmethylimipramine on plasma norepinephrine, pulse, and blood pressure.

We followed the effects of a tricyclic antidepressant selective for norepinephrine (NE) uptake inhibition, desmethylimipramine (DMI), on blood pressure, heart rate, and plasma NE level in healthy subjects. After a single oral dose of 100 mg DMI, supine systolic and diastolic blood pressure and supine and upright heart rate rose, and there was an increment in heart rate with standing. After long-term low doses of the drug (mean daily dosage 67.5 mg), the upright level and increment with standing in plasma NE also rose. Supine NE levels also rose after the long-term higher dose (mean daily dosage 125 mg). No differences in any measures were detected between the short- and the two long-term dose levels of DMI. Our findings suggest that NE uptake inhibition induces physiologic elevation of NE concentration in the sympathetic neuroeffector region. A similar effect at synapses in the CNS might be involved in the mechanism of antidepressant action.

Active metabolites of imipramine and desipramine in man.

Active hydroxy metabolites of imipramine (IMI) and desipramine (DMI) have been quantified in plasma and cerebrospinal fluid (CSF) from patients at steady-state. In plasma of prepubescent boys and adults the concentration of unconjugated 2-hydroxyimipramine is only 15% to 25% that of IMI; 2-hydroxydesipramine (OH-DMI) concentration, however, is usually 50% that of DMI and in some cases OH-DMI is the predominant compound. In CSF from adult patients the ratio of concentrations of OH-DMI/DMI is higher than in plasma. Judging from the CSF/plasma ratio 12% of DMI exists in the free form at steady state, whereas 16% of OH-DMI is free (P less than 0.02). There is no evidence for saturation of hydroxylation within the therapeutic dose and concentration ranges investigated. On the basis of a steady-state OH-DMI/DMI ratio of less than 1/30 in plasma 5% of the population studied could be classified as deficient DMI hydroxylators. This in the same as the incidence of deficient debrisoquine hydroxylators reported in other populations.

Use of ECT with treatment-resistant depressed patients at the National Institute of Mental Health.

The authors review the use of ECT with nine seriously depressed patients at the National Institute of Mental Health over the past 8 years. Despite the patients' poor prior response to a variety of pharmacological treatments, only one patient failed to show a complete response to ECT. With most patients, improvement was quite rapid and dramatic, and all of the ECT responders were free of depression for at least 1 year after treatment. These results are consistent with previous studies; they deserve reemphasis now in light of recent controversies over ECT, including legislative and judicial attempts to restrict its use.

Fluoxetine: a suitable long-term treatment.

A review of fluoxetine's safety profile, especially during long-term treatment, is presented. Key safety advantages for fluoxetine include lower adverse events and dropout rates compared with tricyclic antidepressants and other selective serotonin reuptake inhibitors (SSRIs), safety in overdose, and safe use in special population groups such as women in pregnancy. Prospectively ascertained pregnancy outcomes following exposure to SSRIs, mainly fluoxetine, consistently show no teratogenic effects as assessed in the postnatal period and in comparison with controls. An additional advantage of fluoxetine is the absence or mildness of discontinuation symptoms following treatment interruption, probably a consequence of fluoxetine's long half-life in comparison with other SSRIs. The available data on these topics confirm the suitability of long-term fluoxetine treatment.

Lithium-induced male sexual impairment: two case reports.

Two cases of male sexual dysfunction associated with lithium therapy for major affective disorder, bipolar type I, are reported. One patient received a blind placebo substitution, with rapid disappearance of dysfunction. The second patient presented similar symptoms, which remitted spontaneously on continued lithium therapy. Since lithium is among the most effective and frequently used treatments for affective illness, such side effects, previously considered rare, may be expected to increase in frequency.

Screening hallucinogenic drugs II. Systematic study of two behavioral tests.

The effects of hallucinogenic and nonhallucinogenic drugs were studied on two behavioral tests: (1) discriminated Sidman avoidance, using modified Bovet-Gatti profiles, which have been proposed as specific in detecting hallucinogenic activity and (2) a drug discrimination experiment. By the first method, the "hallucinogenic profile" was obtained with both hallucinogenic and nonhallucinogenic drugs and, at least as used here, was not a suitable screening method. In the drug discrimination experiment, data from the present study along with other available evidence suggest the potential value of this method for drug screening procedures.

Effects of 5-hydroxytryptophan, oxotermorine, and tetrahydroaminoacridine on apomorphine-induced stereotypy.

The stereotyped behavior induced by apomorphine in rats was inhibited by oxotremorine and tetrahydroaminoacridine (THA). 5-Hydroxytryptophan (5-HTP) did not change stereotypy scores. These data show influence of cholinergic mechanisms on such behavior. Possible clinical applications are discussed.

The dexamethasone suppression test: its relationship to diagnoses, severity of depression and response to treatment.

1. The dexamethasone suppression test (DST) was applied to 40 depressed patients, 40 healthy volunteers and 40 patients with other psychiatric disorders. 2. The post-dexamethasone cortisol level, adopted as the non-suppression criterion and established locally, was 3.0 micrograms/dl. 3. The DST sensitivity in depression was 45%, with a specificity of 95% and a positive predictive value of 90%. 4. There was a significant correlation (r = 0.38, p less than 0.05) between HDRS scores of depressed patients and their post-dexamethasone cortisol levels. 5. A prospective study of the depressed group, which was assessed with three depression rating scales, showed differences between non-suppressors and suppressors regarding to the symptoms severity and response to the treatment. It suggests that an abnormal DST result could have a prognostic value to antidepressant drugs and ECT. 6. The DST specificity in depression was also calculated from its performance in the group with other psychiatric disorders, and their diagnoses as well as the abnormal DST results were critically discussed.

The effect of desmethylimipramine on the metabolism of norepinephrine.

Eleven normal volunteers were given an acute and two chronic doses of desipramine (DMI). The plasma norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and dihydroxyphenylglycol (DHPG) concentrations were measured before and during drug administration. DMI reduced plasma concentrations of MHPG by 13% and DHPG by 17%. After two weeks of drug administration, the MHPG/NE ratio was reduced, and there was a significant negative correlation with the concurrent drug concentration. These results suggest that DMI: (1) reduces the turnover of NE; and (2) diminishes the oxidative deamination of NE. In addition, the drug concentration response relationship indicates that the effects of uptake inhibition may not be maximal until concentrations in the apparent therapeutic range are achieved.

Moclobemide effects on prolactin plasma levels in healthy individuals: the hormonal increase induced by a single dose is maintained during a 4-week period of drug intake.

Neuroendocrine challenge studies are frequently used to study the pathophysiology of psychiatric illnesses and the effects of psychotropic drug treatment on brain monoamine function. Moclobemide, a reversible inhibitor of monoamine oxidase, with predominant effects on the A-type of the enzyme, was administered to 15 healthy men. Seven out of the 15 also received single blind placebo a week before the moclobemide. The individuals received moclobemide as a single dose (150 mg), followed by doses of 150 mg three times a day, during a 4-week period. Plasma prolactin was measured in the morning over a 150-min period, following the single dose, and then at the end of weeks 1, 2 and 4 of moclobemide intake. The present data show an acute and transitory increase of plasma prolactin levels after the single dose, and also during the long-term moclobemide administration. It might indicate that steady-state moclobemide levels, during the long-term drug administration, were low and thus large fluctuations of drug levels occurred between doses. Thus, it is suggested that larger doses or administering smaller doses more frequently, or both, may induce hyperprolactinaemia with clinical consequences.

Effects of desipramine and total sleep deprivation on hormonal levels of healthy subjects.

Plasma prolactin (PRL) and growth hormone (GH) were serially measured over a 5-hour morning period in healthy subjects who twice received a single oral dose of 100 mg desipramine (DMI). The study was carried out both after a regular night of sleep and after 1 night of total sleep deprivation. Clinical studies have suggested that sleep deprivation could potentiate the therapeutic effects of antidepressants, and there were reports on DMI stimulation of GH. The basal PRL levels decreased after sleep deprivation, but subsequently increased after DMI, whereas the same dose of DMI did not affect PRL in the absence of after DMI, whereas the same dose of DMI did not affect PRL in the absence of sleep deprivation. The GH levels increased substantially (8- to 10-fold) after DMI in both experimental conditions. Sleep deprivation neither changed GH basal levels nor potentiated the DMI-induced GH increase.

Clinical utility of the premenstrual assessment form as an instrument auxiliary to the diagnosis of premenstrual dysphoric disorder.

The Premenstrual Assessment Form (PAF) is a retrospective self-report questionnaire, yielding classification into syndromal categories and severity assessment (unipolar summary scales) of behavioral, psychological and physical premenstrual changes. However, the PAF has been criticized due to an overlap of its syndromal categories and the unipolar summary scores from symptomatic and asymptomatic women. PAF data from women seeking treatment for premenstrual symptoms and meeting a provisional diagnosis of premenstrual dysphoric disorder (PMDD; n=30) were compared to a control group (n=16). Results showed that 97% of the symptomatic group met the PAF depressive premenstrual syndrome criteria vs. only 12% of the control subjects (chi(2)=29.9, P<0.001). The symptomatic group also reported more severe premenstrual symptoms in all unipolar scales than the control subjects. Sixteen symptomatic women completed two menstrual cycles of prospective daily ratings, and half of them had their provisional diagnosis of PMDD confirmed. There were no significant differences in the scores of the PAF unipolar summary scales between the subgroups with or without the diagnosis confirmation. Most of the PAF scales displayed high sensitivity, but low specificity. These findings suggest that the PAF can be useful to differentiate clinical population and control samples, but it does not provide information to make a more definite diagnosis of PMDD.