LSD in mice: abnormalities in meiotic chromosomes.

Meiotic chromosomes of six mice injected with high doses of lysergic acid diethylamide (LSD-25) and of six controls were studied. Several breaks, gaps, and unidentifiable fragments were found in the treated but, with a few exceptions, not in the control animals. Secondary constrictions were more numerous in the treated than in the untreated mice. Possible consequences are discussed.

Cannabis and alcohol: effects on stimulated car driving.

The effects of cannabis and alcohol on simulated car driving were studied. Cannabis resin containing 4 percent Delta(1)-tetrahydrocannabinol was administered orally in three doses equivalent to 8, 12, and 16 milligrams of that component. Alcohol was given orally in one standard dose of 70 grams. Both cannabis and alcohol increased the time required to brake and start, whereas alcohol increased while cannabis decreased the number of gear changes. An effect of dosage on response was observed with cannabis.

Histocompatibility antigens and manic-depressive disorders.

Forty-seven unrelated Danish patients considered to be manic-depressive, according to strict diagnostic, symptomatic, and course criteria, were typed for histocompatibility (HLA) antigens. Significantly more manic-depressive patients than controls were found to have HLA-A3, HLA-B7, and HLA-Bw16, while significantly fewer manic depressives than controls had HLA-B8. All eight of the patients with HLA-Bw16 were bipolar patients, and none were unipolar depressive patients. We emphasize the need to consider the results with caution in view of the large number of antigens considered and the relatively small number of patients involved. When statistical corrections are made for the large number of antigens investigated, only the difference between bipolar patients and controls remains significant. The best way to determine if our findings are really significant is to attempt to confirm them in other series of patients. The importance of utilizing strict symptomatic and course criteria for the selection and polarization of proband is stressed.

ABO blood groups in unipolar and bipolar manic-depressive patients.

The authors determined ABO blood groupings for 66 manic-depressive patients diagnosed and divided into bipolar and unipolar groups according to strict symptomatic and course criteria. A significantly higher percentage of bipolar patients than unipolar patients had blood group O, while a significantly higher percentage of unipolar patients than bipolar patients had blood group A. THese findings provide support for the validity of the unipolar-bipolar distinction and are consistent with the concept that vulnerability to manic-depressive disorders may be related to membrane disturbances.

Effect of lithium on reaction time--a study of diurnal variations.

Continuous reaction time performance was measured in groups of normal controls, psychiatric controls and patients treated with lithium. The reaction times were slower for the patients treated with lithium compared to both groups of controls, but the performance was not impaired to the same degree as in patients with various forms of cerebral dysfunction. For all groups reaction times were slower in the morning than in the evening or at night. Slow reaction times at the first investigation in the groups of normal and psychiatric controls were positively correlated with larger variations in the 24 h course. However, this correlation could not be demonstrated for patients on lithium treatment, probably because these patients do not approach their limit of speed as often as other patients or controls.

Assessment of the anticholinergic effects of antidepressants in a single-dose cross-over study of salivation and plasma levels.

In order to evaluate the anticholinergic effect of antidepressant drugs, 11 healthy volunteers were given single oral doses of reference drug, test drugs or placebo on a double-blind basis at weekly intervals. The doses corresponded to average daily patient medications. Spontaneous whole mouth and parotid salivation, and plasma levels of drug and possible metabolites were measured 2, 6 and 10 h after drug administration. Moderate, statistically significant inhibition of salivation was found when nortriptyline, imipramine-N-oxide and mianserin were given. Less pronounced, but still statistically significant inhibition occurred after ingestion of nomifensine and zimelidine. The zimelidine effect was exclusively due to the metabolite norzimelidine, and the inhibition after imipramine-N-oxide was mainly due to the metabolite imipramine, but imipramine-N-oxide itself also had slight activity. Isocarboxazide and lithium had no effect on salivation. From these results and reported values of pharmacokinetic variables, the average level of anticholinergic activity during long-term treatment may be predicted: for mianserin and (nor-)zimelidine moderate inhibition of salivation, although less pronounced than with nortriptyline; for nomifensine no clinically significant effect; and for imipramine-N-oxide a negligible contribution from the unmetabolized drug.

Lithium treatment regimen and renal water handling: the significance of dosage pattern and tablet type examined through comparison of results from two clinics with different treatment regimens.

For many year two Danish psychiatric hospitals having used different lithium treatment regimens. In one, slow-release tablets were given in two daily doses and, in the other conventional tablets were given in a single daily dose. In both hospitals many patients developed polyuria. Multiple regression analyses with sex, age, treatment duration, serum lithium concentration, and treatment regimen as predictor variables showed that the two treatment regimens did not affect the glomerular filtration rate or the proximal reabsorption differently, but that distal water reabsorption was significantly less affected and polyuria less pronounced in the patients given conventional tablets once daily than in those give slow-release tablets twice daily. The authors are divided among themselves as regards the implications of these findings.

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.

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.

Neuropeptides in the cerebrospinal fluid (CSF) in psychiatric disorders.

Concentrations of vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK) and gastrin in the cerebrospinal fluid (CSF) was studied in patients with endogenous depression, non-endogenous depression, mania, schizophrenia and a control group. All patients were classified according to various diagnostic systems. In the group of non-endogenously depressed patients CSF-VIP levels (median 16 pmol/l) were found significantly lowered compared to controls (median = 32 pmol/l) and endogenous depression (26 pmol/l). Going through the non-endogenous group it appeared that the low CSF-VIP was due to a group of patients with a former diagnosis of endogenous depression or a present diagnosis of possible endogenous depression. Moreover, this group was clinically characterized by 'dysphoric/hysterical features', 'reversed diurnal variation' (i.e. worst in the evening), and 'lack of clearly circumscribed episode'. In many aspects this group seems similar to the atypical depressions described as monoamineoxidase responders. Concerning CSF-CCK and CSF-gastrin no significant differences between the examined groups were demonstrated.

Nocturnal temperature in affective disorder.

The temperature rhythms of 9 drug-free patients with primary affective disorder were measured during depression and after recovery and compared with those of 12 normal controls. The patients had higher nocturnal temperatures and decreased 24-hour amplitudes when depressed than when they had recovered and compared to the controls. There was no evidence that the temperature minimum occurred earlier in the night in depression compared to controls. However, in 4 of 7 patients the temperature minimum occurred earlier in the night during depression compared to recovery.

The dexamethasone suppression test in depression.

The Dexamethasone Suppression Test (DST) was performed in 91 patients (depressive, manic and schizophrenic) and 11 healthy control persons. It was found that more endogenously depressed patients than non-endogenously depressed patients showed abnormal test results. The results were markedly influenced by the time of blood sampling, the diagnostic criteria and the plasma cortisol concentration threshold.

Diurnal variation of blood glucose during lithium treatment.

Plasma glucose was analysed during a 24-hour period in 62 lithium-treated patients. Compared with 59 normal control persons and 80 psychiatric controls the lithium-treated patients with neutral mood had higher maximum glucose and higher mean plasma glucose. Depressed lithium-treated patients had lower mean plasma glucose than the neutral lithium-treated patients. Depressed patients among the psychiatric controls did not differ from the neutral patients in this group with respect to plasma glucose.

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.

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.

Vasoactive intestinal polypeptide decreased in cerebrospinal fluid (CSF) in atypical depression. Vasoactive intestinal polypeptide, cholecystokinin and gastrin in CSF in psychiatric disorders.

Vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK) and gastrin in the cerebrospinal fluid (CSF) were studied in patients with endogenous depression, non-endogenous depression, mania, schizophrenia and a control group. All patients were classified according to ICD-9 and the group of depressions was further classified according to the Newcastle Rating Scales for depression (Carney et al. 1965) (N-I). In the group of non-endogenously depressed patients, CSF-VIP levels (median 16 pmol/l) were found to be significantly lower than those of controls (median = 32 pmol/l) and endogenous depressives (36 pmol/l). In the non-endogenous group, it appeared that the low CSF-VIP was due to a group of patients who, during a past or present depressive episode, had been diagnosed as suffering from endogenous depression. Moreover, this group was clinically characterized by 'dysphoric/hysterical features', 'reversed diurnal variation' (i.e. worse in the evening), and 'lack of clearly circumscribed episodes'. In many aspects this group seems similar to the atypical depressives described as monoamine oxidase inhibitor responders. Concerning CSF-CCK and CSF-gastrin, no significant differences between the examined groups were demonstrated.

The Hamilton Anxiety Scale. Evaluation of homogeneity and inter-observer reliability in patients with depressive disorders.

In the present study the Hamilton Anxiety Scale (HAS), originally constructed for patients with neurotic anxiety, has been applied to patients with diagnosis of depressive disorders. The inter-rater reliability and homogeneity are evaluated and total scale score has been correlated to the Bech-Rafaelsen Melancholia Scale (BRMES). Twenty-two patients entered the study, 13 with endogenous depressions, and 9 with non-endogenous depressions when classified according to the ICD-8. For both scales the inter-rater reliability was found statistically significant. Concerning the homogeneity of the HAS, statistical significance was obtained for 7 items reflecting psychic anxiety, whereas in the BRMES statistical significance was found in all items apart from 2. Total scale score on HAS correlated positively with total score on BRMES for all 2 patients. However, when the patients were classified according to the ICD-8 this correlation seemed to be due to the endogenously depressed group as no significant correlation was seen for the group of non-endogenous depression. On the other hand, when the patients were classified according to the MULTI-CLAD system no significant intercorrelation of the HAS and BRMES scores was found within the subtypes of depression.

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.

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.

Magnesium concentrations in blood and cerebrospinal fluid during delirium tremens.

Magnesium in plasma, erythrocytes, and cerebrospinal fluid (CSF) was measured immediately after hospital admission in 9 patients with delirium tremens (DT) and 11 patients with impending DT. Blood samples were taken daily during the acute state; a second lumbar puncture was performed when the patient's condition had improved. Plasma magnesium was low in patients with DT during the first days of the acute state and then spontaneously normalized. Normal plasma magnesium was consistently seen among patients with impending DT. Magnesium in erythrocytes and CSF was normal in both diagnostic categories. Patients with a high blood-alcohol concentration (BAC) at admission had a decreasing plasma magnesium, patients with a low BAC had a moderately increasing plasma magnesium, and patients with a BAC at nil had a more marked increase in plasma toms or with their duration. This finding, combined with the normal CSF magnesium and the lack of correlation between plasma and CSF magnesium, indicates that disturbances in magnesium metabolism do not play a role in the etiology or pathogenesis of DT; but it may be that disturbances in magnesium metabolism contribute to the development of alcoholic encephalopathy.