The oral dose-effect relationship for fluvoxamine: a fixed-dose comparison against placebo in depressed outpatients.

This 7- to 8-week, multicenter, randomized, double-blind, placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder. Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects. The study enrolled 600 outpatients, male and female, age 18-65, meeting DSM-III-R criteria for major depressive disorder. A 13-item subscore of the standard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score. Secondary efficacy assessments included the HAM-D retardation factor, HAM-D depressed mood item, CGI-severity of illness item, and SCL depression factor. Fluvoxamine (50-150 mg/day) was therapeutically effective and well tolerated during 6 weeks of therapy. Based on the HAM-D depressed mood item, efficacy was dose dependent. The minimum effective dose was 50 mg/day. Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder.

A comparison of venlafaxine, trazodone, and placebo in major depression.

A double-blind, placebo-controlled trial was undertaken to compare the safety and efficacy of venlafaxine and trazodone in patients with major depression. Two hundred twenty-five patients entered an initial 6-week treatment phase, and 149 completed it. Ninety-six patients who were responders continued in a 1-year, double-blind, long-term phase during which they received the same medication and doses they had during the short-term phase. Both active treatments were significantly more effective than placebo on some measures during the short-term study, but venlafaxine produced more improvement in the cognitive disturbance and retardation factors on the Hamilton Rating Scale for Depression. Trazodone was more effective against the sleep disturbance factor. Patients on venlafaxine were most likely to enter the long-term phase and to remain in the trial longest. The side effect profiles of the three treatment groups were compared. Venlafaxine was most likely to cause nausea, whereas trazodone was associated with the most dizziness and somnolence.

A controlled study of mianserin in moderately to severely depressed outpatients.

Following a 1-week, single-blind placebo washout, 150 patients were randomized to double-blind treatment with daily doses of either mianserin, 30 mg to 150 mg; amitriptyline, 60 mg to 300 mg; or placebo, 1 to 5 capsules taken at bedtime (qhs). Mianserin and amitriptyline were found to be comparable in efficacy, and both significantly more effective than placebo in the treatment of major depressive illness. Rating instruments, all of which showed significant improvement in the active drug groups over the placebo, included the 17- and 21-item Hamilton Rating Scale for Depression (HAM-D), Montgomery and Asberg Depression Rating Scale (MADRS), Self-rating Depression Scale (SDS) index, and the Clinical Global Impressions (CGI) Severity of Illness and Improvement rating scales. Furthermore, for most efficacy parameters in the efficacy-evaluable group, the earliest statistically significant difference vs. placebo could be observed at Visit 1 for the mianserin patients and at Visit 3 for the amitriptyline patients. The safety profile for mianserin was comparable with placebo with respect to laboratory values, electrocardiogram changes, vital signs, ophthalmologic evaluations, and most adverse clinical experiences. Complaints of somnolence and weight gain were comparable in the amitriptyline and mianserin groups. Mianserin was superior to amitriptyline in terms of vital signs; anticholinergic effects; and complaints of dizziness, dyspepsia, and tremor.

A fixed-dose (300 mg) efficacy study of bupropion and placebo in depressed outpatients.

Two hundred twenty-four outpatients with major depression entered a 6-week, five-center, double-blind trial of bupropion 300 mg/day and placebo. A total of 216 patients were included in the efficacy analysis. In the combined center analysis, greater efficacy for bupropion was found on one or more measures (Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions) at treatment Days 21, 28, 35, and 42. Bupropion was well tolerated; only four adverse events were reported at least 5% more often in the bupropion group than in the placebo group. Six bupropion patients versus 5 placebo patients discontinued treatment because of adverse events. This study extends earlier findings of efficacy for higher-dose treatment in an inpatient population to lower-dose treatment in an outpatient population.

Lithium combined with neuroleptics in chronic schizophrenic and schizoaffective patients.

In a placebo-controlled double-blind crossover study lithium carbonate was added to the neuroleptic treatment of 11 chronic schizophrenic and 7 schizoaffective inpatients. Nurses' ratings of behavior indicated significant improvement in 8 patients in agitation or manic behavior, 5 patients in psychosis, and 5 patients in depression. A greater initial severity of symptoms, presence of affective symptoms and episodic course characterized the favorable response group. No neurotoxicity was encountered in this study.

Immunoreactive calcitonin in cerebrospinal fluid of man.

We have detected immunoreactive calcitonin (iCT) in the cerebrospinal fluid (CSF) of normal individuals. Using an antibody with midportion recognition, the mean +/- S.D. of the cerebrospinal iCT in 27 normal subjects was 28 +/- 14 pg/ml. The mean serum iCT was 89 +/- 68 pg/ml, the CSF/serum distribution ratio being 0.31. There were no significant correlations between CSF iCT or serum iCT and the calcium, magnesium, phosphate, sodium, potassium or chloride in the CSF or serum. Although there was a trend for serum iCT values to be related to CSF iCT values, it did not attain statistical significance. The demonstration that the CSF contains iCT may have important physiologic implications, and its measurement offers a useful parameter to study its effects on calcium metabolism and/or other aspects of brain function.

Calcitonin reduces feeding in man, monkey and rat.

It is proposed that calcitonin is a hormonal mediator of the satiety reflex. To test this hypothesis, effects of calcitonin on feeding and drinking were measured in rats and in rhesus monkeys. In monkeys, calcitonin produced severe (90%) and prolonged (3-5 days) reduction in feeding, and smaller decreases in drinking. In rats calcitonin decreased feeding in a dose-related manner over 24 hours, but increased drinking and urine output. A modest loss in body weight (2%) was also observed in psychiatric patients given calcitonin. It is suggested that calcitonin reduces feeding either through its effects on calcium metabolism, or by a direct action on the central nervous system.

Calcium: pacesetting the periodic psychoses.

In this double-blind study dihydrotachysterol (DHT) was given orally to eight psychotic patients; in each case marked increases in psychosis and agitation accompanied increases in serum calcium and phosphorus within two weeks after active drug was substituted for placebo. In the three patients whose psychoses exhibited periodic spontaneous exacerbations, the agitated episodes grew more severe. Serum creatine phosphokinase (CPK) increased in all but one patient. By contrast, when three periodically psychotic patients received synthetic salmon calcitonin (SCT), the severity and frequency of agitated episodes decreased while CSF calcium increased in all three. These data support the hypothesis that the observed abrupt increases in serum calcium and phosphorus might cause the opposite CSF calcium shifts, the behavioral agitation and the increases in serum CPK frequently noted during acute psychosis.

Increased serum calcium and phosphorus with the 'switch' into manic or excited psychotic state.

Small but statistically significant increases in serum total calcium and serum inorganic phosphorus concided with repeated onsets of psychotic agitation or mania in nine psychotic in-patients experiencing rapid cycles of illness. These increases were not accompanied by changes in magnesium or other constituents, which might suggest non-specific haemoconcentration. Similar increases in calcium or phosphorus were not present in patients without the same cycles of psychotic illness. The observed increases could neither be simulated nor altered by stress or activity, and it remains unclear whether they might be accounted for by dietary changes, sleep disruption, circadian phase shifts or by endocrine alterations.

Calcium: bivalent cation in the bivalent psychoses.

Decreases in cerebrospinal fluid (CSF) calcium accompany mood elevation and motor activation in depressed patients undergoing treatment with ECT, lithium, and total sleep deprivation. Similarly, decreases in CSF calcium occur during acute psychotic agitation or mania. On the other hand, periodic recurrences of such agitated states are accompanied at their onset by transient increases in serum calcium and phosphorus. Several observations suggest that such serum ion shifts may trigger the more enduring and opposite shifts in CSF calcium and, in turn, the manic behavior. Progressive restriction of dietary calcium was earlier reported to mitigate and finally abolish both rhythmic rises in serum calcium and periodic agitated episodes in one psychotic patient. Lithium, which decreases the efficiency of alimentary calcium absorption, may function similarly. Conversely, a modest oral calcium lactate supplement (approximately one additional Recommended Daily Allowance of dietary calcium) seemed to slightly intensify agitation in six patients. Dihydrotachysterol (DHT), an analogue of vitamin D, which more exactly mimics the increase in both serum calcium and phosphorus, appeared in at least one periodically psychotic patient to trigger and opposite shift in CSF calcium. Moreover, in eight patients, manic symptomatology appeared de novo or grew significantly and substantially worse during 2 to 6 weeks of oral DHT administration. On the other hand, in 12 patients, subcutaneous injections of synthetic salmon calcitonin (SCT) decreased serum calcium and phosphorus, increased CSF calcium, and decreased agitation while augmenting depressive symptomatology. SCT also decreased quantified motor activity, frequency and severity of periodic agitated episodes, serum CPK and prolactin, and nocturnal sleep, while DHT or calcium lactate had opposite effects on the same parameters.

CSF calcium: clinical correlates in affective illness and schizophrenia.

In a study of electrolytes in lumbar cerebrospinal fluid (csf) from psychiatric patients, the authors found a positive correlation between calcium concentration and symptom severity in hospitalized depressed patients. CSF calcium levels tended to decrease as patients improved. In four rapidly cycling patients, CSF calcium was higher during depression than during mania. Mean CSF calcium for the depressed patients as a group was not significantly different from neurological controls or other psychiatric patients. Symptom remission from acute psychosis in schizophrenic patients was accompanied by a significant increase in CSF calcium concentration. These findings are discussed in relationship to calcium-induced alterations in neuronal and physiological excitability.

Use of calcitonin in psychotic agitation or mania.

Synthetic salmon calcitonin was administered subcutaneously to 12 inpatients with several primary psychotic diagnoses. Increases in serum total calcium and inorganic phosphorus levels and decreases in CSF calcium level had earlier been observed during periodic psychotic agitation or mania. By contrast, calcitonin, which decreased serum calcium and phosphorus levels and increased CSF calcium level, appeared to produce transient (24-hour) increases in depression and decreases in arousal in this double-blind placebo-controlled trial. Quantitative activity monitoring confirmed the rater's impression that this agent had tranquilizing or depressant effects in such patients. When given in the evening, this polypeptide also appeared to delay sleep onset, as demonstrated both by nurses' 30-minute sleep checks and by the same longitudinal activity record. A decreased hypocalcemic response to calcitonin was noted in the agitated patients, which might explain the increases in serum calcium level described at the "switch".

Effects of a dopamine agonist piribedil in depressed patients: relationship of pretreatment homovanillic acid to antidepressant response.

Piribedil, a compound that stimulates dopamine receptors in a relatively specific fashion, was administered to 11 hospitalized depressed patients. The dopamine agonist significantly decreased rapid eye movement (REM) sleep and percent REM sleep and increased REM latency. Piribedil decreased the probenecid-induced accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF. A range of mild to moderate antidepressant effects was noted; one patient worsened and one developed recurrent manic episodes. The degree of improvement in depression was negatively correlated with pretreatment values of HVA in CSF (r = -.66, P less than .05). These data suggest that the heterogeneity of clinical response may be related to biological differences in depressed patients and that those with low initial dopaminergic function respond best to increased dopamine receptor stimulation.

Calcium and electroconvulsive therapy of severe depressive illness.

In severely depressed patients with primary affective illness, consistent decreases in total calcium concentration have been demostrated in both CSF and serum following successful ECT treatment. The hypocalcemia does not appear to occur after the initial ECTs, but develops after three to five treatments, coincident with an acceleration in clinical antidepressant effects, and is not an artifact of the anesthetic premedications or mechanical ventilation of the patients. Evidence linking alterations in calcium metabolism to mood is reviewed and a number of mechanisms by which the calcium change might result from ECT and mediated its effects on mood are discussed.

The tryptolines: effect of intraventricular administration on spontaneous motor activity of rats.

The pharmacologic properties of the tryptolines, hindered analogues of the tryptamines, were studied behaviorally in rats. Following intraventricular injections, it was found that spontaneous motor activity decreased markedly during the initial 25 mins when compared with saline. Since both the tryptolines and tryptamines have been shown to be inhibitors of 5-hydroxytryptamine uptake, it may be possible that these compounds are acting indirectly throught an effect on the serotonergic system.