A tolerance study of single and multiple dosing of the selective dopamine uptake inhibitor GBR 12909 in healthy subjects.

GBR 12909 selectively blocks dopamine uptake and its biochemical and pharmacological profiles suggest that it may possess antidepressant activity and be of value in treatment of Parkinson's disease. The tolerance, pharmacokinetics and influence on psychomotor performance of GBR 12909 were investigated in a randomized placebo-controlled double-blind study. Four healthy subjects were administered oral single doses of 100, 200 and 300 mg GBR 12909 and placebo, and four other healthy subjects received, 50, 100 and 150 mg GBR 12909 and placebo once daily for 7 days. The intermediate and highest doses resulted in mild to moderate side-effects such as difficulties in concentrating, asthenia, feeling of drug influence and palpitations. No changes were observed in haematological and clinico-chemical parameters. A dose-related effect on ECG was observed with a slight reduction of the T-wave amplitude. No signs of arrhythmia or decompensation during exercise until exhaustion were observed. Psychomotor performance indicated dose-related sedation in the single-dose study. Only minor deviations from first order kinetics were observed. Elimination half-life was estimated at 1-2 days. Steady-state serum concentrations of GBR 12909 appeared to be attained within 1 week. Based on the results of this study, the estimated therapeutic doses are expected to be well-tolerated in patients.

Effect of nifedipine on the shuttlebox escape deficit induced by inescapable shock in the rat.

The behavioural effect of subchronic treatment with calcium channel antagonists (nifedipine, verapamil) and with imipramine was assessed in rats subjected to inescapable shock (IS). The effect of subchronic treatment with nifedipine and imipramine on specific [3H]nitrendipine ([3H]NDP) binding was investigated in frontal cortex of naive rats and in rats given IS then tested for shuttlebox escape. The rats showed a severe impairment in escape behaviour after IS. Imipramine and nifedipine significantly reduced FR1 and FR2 escape deficits. Verapamil had no effect. A small but significant increase in the number of [3H]NDP binding sites (Bmax) was seen in rats exposed to the shuttlebox escape test independent of a previous exposure to IS. Imipramine had no influence on Bmax in any of the groups. Nifedipine did not affect [3H]NDP binding in naive rats but decreased Bmax in rats subjected to IS and the shuttlebox escape test. The comparable ability of nifedipine and imipramine to reverse the shuttlebox escape deficit induced by IS argues for a possible antidepressant activity of nifedipine. The biochemical data indicate that cortical [3H]NDP binding sites are not correlated to performance in the shuttlebox escape test.

The Diagnostic Melancholia Scale (DMS): dimensions of endogenous and reactive depression with relationship to the Newcastle Scales.

The two diagnostic Newcastle Scales for depression have been evaluated in a drug trial with antidepressants. By use of latent structure analysis (Rasch models) it was found that two dimensions are necessary for describing the diagnosis of depression, one for endogenous features and one for reactive features. Of the depressed patients 50% had a pure endogenous depression, 14% had a pure reactive depression, 32% had mixed endogenous and reactive depression, and 4% had uncertain diagnosis. In the pure endogenous depression group 77% had a monotonically non-decreasing improvement curve during treatment whereas in the other diagnostic categories around 50% had such an improvement.

Treating depression in acute stage: biochemical and clinical aspects.

The treatment of depression has advanced dramatically over the last 50 years: electroconvulsion, monoamine oxidase inhibitors (MAOIs), cyclic antidepressants - in chronological order. The amine theories have been giving guidance in the development of new antidepressant drugs and have thus been important in the selectivity of drugs acting, for example, primarily on 5-hydroxytryptamine (5-HT) reuptake. Drugs like citalopram, fluoxetine, fluvoxamine, and paroxetine are very selective in their 5-HT reuptake inhibition, so that in clinical practice they can be tested for the specific importance of this system in depression. Research on cerebrospinal fluid (CSF) has for many years been restricted to amine metabolites, but we have now been able to measure the parent neurotransmitters, thanks to international cooperation. CSF adrenaline was low, noradrenaline normal, and serotonin and dopamine increased in untreated depression. This calls for major revision of the amine theories. In addition, our animal studies have shown marked increase in CSF adrenaline after MAOIs, and long-term effect of citalopram on CSF noradrenaline. This indicates the need for enlargement of the number of transmitters in the elucidation of the biology of depression and its treatment, and that interactive counterregulations may lessen the initial selectivity of antidepressant drugs.

CSF dopamine increased in depression: CSF dopamine, noradrenaline and their metabolites in depressed patients and in controls.

Some studies report reduced levels of the dopamine metabolite HVA in CSF in depression. In the present study including 24 depressed patients and 10 controls, we found significantly increased concentrations of total CSF dopamine in depressed patients. This finding suggests a dysfunction in central dopamine turnover in depression. No differences in CSF levels of noradrenaline or the amine metabolites homovanillic acid and 3-methoxy-4-hydroxy-phenylglycol were seen when comparing depressed patients with controls.

Lithium: long-term effects on the kidney. IV. Renal lithium clearance.

Renal lithium clearance was investigated in 44 patients treated with lithium for an average of 8 years as part of a functional-morphological follow-up study including a kidney biopsy. The average renal lithium clearance was 0.36 ml/s (= 21.6 ml/min). A significant correlation with age, sex and glomerular filtration rate was seen, whereas no significant relationship with urine volume, lithium treatment regimen and histopathological biopsy variables was found. The results were compared with the same renal functional tests obtained from a control group consisting of 26 patients with affective disorders never treated with lithium. The control group had a lower urine output, but no significant difference in lithium clearance was observed. In conclusion, renal lithium clearance is a specific investigation, which may provide valuable baseline information on glomerulo-tubular function in patients before and during prophylactic lithium treatment.

CSF-amine metabolites in depression, dementia and in controls.

Lumbar CSF concentration of 5-HIAA, MHPG, and HVA were measured in patients with depression, dementia due to normal pressure hydrocephalus (NPH) and in controls. Moreover, ventricular concentrations of the metabolites were measured in patients with NPH. It was aimed to match patients and controls for age, sex, and body height. Non-parametric statistics were used throughout the study. No differences in lumbar concentrations of CSF 5-HIAA, MHPG and HVA were found between the different diagnostic groups. A ventriculo-lumbar gradient of 5-HIAA and HVA being 4:1 and 5:1, respectively, was found in patients with NPH. No correlation between the difference in ventricular and lumbar concentrations and body height was found, suggesting that body height may be an inaccurate measure for the rostro-caudal gradient. Moreover, no correlation between ventricular and lumbar levels of 5-HIAA and HVA was seen.

CSF-adrenaline--low in "somatizing depression".

Cerebrospinal fluid (CSF) adrenaline and noradrenaline were measured in 14 depressed patients and in seven controls. CSF-adrenaline, but not noradrenaline, was significantly reduced in the depressed patients. Moreover, a significantly negative correlation between "anxiety, somatic", "hypochondriasis", evaluated as single items on the Hamilton Depression Scale, and CSF-adrenaline concentrations, was found.

Lithium: long-term effects on the kidney. III. Prospective study.

Renal function in 32 patients treated with lithium for an average period of 10 years was reexamined 2 years after the first examination. A markedly influenced tubular function leading to increased urine volume (average 3 litres/24 h) and decreased renal concentrating capacity was still found, whereas glomerular function remained unimpaired in nearly all of the patients. No statistically significant changes in renal functions were observed at the follow-up examination. The results were compared with the same renal functional tests obtained from a control group consisting of 53 patients with affective disorders never treated with lithium. The control group had a significantly lower urine output (average 2 litres/24 h), but lithium-treated patients on a one-dose schedule had an average urine volume of only 500 ml/24 h more than the controls. In conclusion, this prospective study found no evidence of a progressive impairment of glomerular or tubular function in lithium-treated patients reexamined after 2 years. Patients with affective disorders never treated with lithium had normal renal concentrating capacity.

Lithium: long-term effects on the kidney--II. Structural changes.

Forty-six patients treated with lithium for an average of 8 yr participated in a follow-up study involving a kidney biopsy. The results were compared with renal biopsy specimens from an age-matched group of controls never treated with lithium. The average number of totally scelerotic glomeruli and atrophic tubuli was higher in lithium-treated patients. The histopathological changes showed significant correlations with lithium dosage schedule. Both the proportions of sclerotic glomeruli, atrophic tubuli and focally distributed interstitial fibrosis were higher in patients receiving their lithium two or three times a day than when lithium was given in a single daily dose.

5-HT and 5-HIAA in cerebrospinal fluid in depression.

CSF 5-HT and 5-HIAA were measured in endogenously depressed patients (ICD-9) (n = 23) and controls (n = 11). Distribution of sex, age and body height was similar in the two groups. Non-parametric statistics were used. In depressed patients CSF 5-HT concentrations were found to be higher (P less than or equal to 0.01) than in controls. A further classification of the depressed patients by the Newcastle Scale showed that the highest values were found in the endogenous group compared to the non-endogenous group (P less than or equal to 0.02). CSF 5-HIAA was found to be equal in the two groups, even when pairs matched for height were compared. No relation between clinical recovery due to drug treatment and changes in CSF 5-HT was seen. Our data support a possible involvement of 5-HT in the biology of depression, but the anatomical and functional levels of a serotonin derangement are still unknown.

Rating scales for states for anxiety, depression, mania and schizophrenia. A multiaxial approach.

Rating scales are considered to be an efficient instrument in the assessment of treatment effect, and during the last 25 years a number of rating scales has been constructed for measuring states of anxiety, depression, mania and schizophrenia. The paper describes some of the most frequently used scales. Time has come to coordinate the existing rating scales and to agree upon common operational definitions in the judgement of psychopathological symptoms. Basic practical guidelines to be used in both clinical practice and research are given.

REM latency and core temperature relationships in primary depression.

REM latency and rectal and ear canal temperature were studied simultaneously in 11 controls and nine depressed patients; seven of the patients were studied when recovered. REM latency was shorter in the depressed group compared with controls and lengthened with recovery. The nocturnal and ear canal temperatures were higher in the depressed group compared with controls and decreased with recovery. REM latency and the nocturnal rectal temperature were negatively correlated when all the nights of the depressed patients were analyzed (r = -0.44) and when all the nights of the subjects were analyzed (r = -0.44). REM latency and nocturnal ear canal temperatures were negatively correlated when all the nights of the control group were analyzed (r = -0.34). The timing of the temperature rhythm did not appear to be correlated with the REM latency.

Lithium: long-term effects on the kidney. I. Renal function in retrospect.

46 patients treated with lithium for an average of 8 years participated in a functional-morphological follow-up study based on a 12-day hospitalization and involving a kidney biopsy. The functional part of the study showed that tubular function was markedly influenced, leading to increased urine volume (average 3 1/24 h) and a decreased renal concentration capacity in 85% of the patients. Glomerular function was generally not influenced, and only 10% of the patients had glomerular filtration rates below their age-corrected normal ranges. Both urine volume and glomerular filtration rates showed significant correlations with dosage schedule. Urine volume was lower and glomerular filtration rate higher on a one-dose schedule than when lithium was given in divided doses during the day. It is concluded that discontinuity in lithium treatment minimizes lithium effects on kidney function.

The TRH stimulation test and the dexamethasone suppression test in depression.

The thyrotropin-releasing hormone (TRH) stimulation test and the dexamethasone suppression test (DST) were performed in 40 depressive patients. More endogenously depressed patients than nonendogenously depressed patients showed a blunted response to TRH. No difference was found in delta max thyroid-stimulating hormone (TSH) between patients who responded to dexamethasone administration with a normal suppression of cortisol and those who responded with nonsuppression.

Femoxetine and cimetidine: interaction in healthy volunteers.

The possibility of a pharmacokinetic interaction between femoxetine and cimetidine has been evaluated in 8 healthy volunteers. Two volunteers received single doses of femoxetine, and 6 were given multiple doses of femoxetine for 7 days with and without concurrent cimetidine. No influence of cimetidine was observed on the kinetics of single doses of femoxetine, but after multiple doses the plasma concentration of femoxetine was significantly increased. Similarly, the AUC at steady state tended to be increased, but not to a significant extent. Concurrent cimetidine did not cause a reduction in the AUC of the active desmethyl metabolite. It is recommended that femoxetine is given in reduced doses (e.g. 400 mg) when administered with cimetidine.