Acute antidepressant effect of lithium is associated with fluctuation of calcium and magnesium in plasma. A double-blind study on the antidepressant effect of lithium and clomipramine.

In a double-blind study on 22 patients with major depressive disorder the effects of lithium and clomipramine on signs and symptoms and on calcium and magnesium in plasma were compared. Ratings of antidepressant and side effects were performed by 2 psychiatrists at the end of a placebo period of 5-7 days and after treatment for 2 and 4 weeks. Psychopathology was rated by 15 reported and 4 observed items from the Comprehensive Psychopathological Rating Scale (CPRS). Eleven items present in 72-100% of the patients were used to evaluate the effect of the two drugs. After 2 weeks of treatment the rated scores dropped for more than half of the CPRS items. After 4 weeks the scores for all but one item were reduced in both groups. The sums of scores were significantly reduced after 2 weeks in both groups and after 4 weeks global scores were reduced as well. The drugs had notable and similar antidepressant effects. Lithium treatment was associated with fluctuations in calcium and magnesium levels in plasma not seen during clomipramine treatment. Serum prolactin increased during clomipramine treatment but was unaffected by lithium treatment. No correlations were found between the sum of rating scores and blood levels of drugs, prolactin, calcium or magnesium.

5-hydroxytryptophol in human cerebrospinal fluid: conjugation, concentration gradient, relationship to 5-hydroxyindoleacetic acid, and influence of hereditary factors.

The serotonin metabolite 5-hydroxytryptophol was studied in human cerebrospinal fluid. A minor fraction (approximately 13%) was found in conjugated form from which it was liberated by treatment with sulphatase containing beta-glucuronidase activity. A concentration gradient of 5-hydroxytryptophol concentration was shown on lumbar tapping and the concentration in ventricular CSF was about 2.5 times higher than that in lumbar CSF. 5-Hydroxytryptophol and 5-hydroxyindoleacetic acid concentrations were significantly correlated in healthy, psychotic, and depressed subjects, but not in alcoholics. 5-Hydroxytryptophol concentrations in CSF of psychotic and depressed subjects were not different from those of healthy controls (4.22 pmol/ml +/- 0.15, SEM). In healthy subjects, hereditary factors seemed to have little influence on the CSF level of 5-hydroxytryptophol.

Relationships in healthy volunteers between secretion of monoamine metabolites in urine, and family history of psychiatric morbidity.

In 66 physically and mentally healthy human subjects the total concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and dihydroxyphenyl acetic acid (DOPAC) in urine collected between midnight and 8 AM were analyzed by mass fragmentography. In the volunteers reporting the occurrence of psychiatric morbidity among relatives an increased variance in their MOPEG levels was found as compared to the volunteers without such a family history. In the male subjects with no family history of psychiatric disease there was a positive correlation between urine and cerebrospinal fluid levels of MOPEG. The urine levels of 5-HIAA, HVA, and DOPAC did not demonstrate any changes that could be related to psychopathology within the family. Changes in urine secretion of MOPEG indicate an altered metabolism of norepinephrine/MOPEG in some subjects with the occurrence of severe psychiatric disease within the family. MOPEG levels in urine may be a predictor of a family vulnerability for psychiatric morbidity in healthy subjects.

Relationships in healthy volunteers between concentrations of monoamine metabolites in cerebrospinal fluid and family history of psychiatric morbidity.

In 60 physically and mentally healthy human subjects, lumbar cerebrospinal fluid was analysed by mass fragmentography for 5-HIAA, HVA and MOPEG. Individuals with a family history of psychiatric morbidity had significantly greater variation in monoamine metabolite concentrations than subjects without such a family history. In subjects with a family history of schizophrenic psychosis 5-HIAA and HVA concentrations were significantly higher than in subjects with depressive disorders within the family. For subjects with deviant 5-HIAA levels the probability of having a psychiatric family history was 2.7 times higher than in subjects with normal values. For HVA and MOPEG similar relationships, but of a lower significance level, were found. The results suggest that the cerebral monoaminergic transmitter amines play critical roles in the pathophysiology of psychotic and depressive disorders with a family disposition. They also indicate a value of monoamine metabolite determination in CSF for the prediction of family vulnerability for psychiatric morbidity in healthy subjects.

Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine.

The clinical effects of chlorpromazine (CPZ) administered in accordance with a double-blind design in one of three doses (200, 400 or 600 mg) were examined in 44 psychotic patients. The relationships between the effects and the CPZ concentrations in plasma and cerebrospinal fluid (CSF) were analyzed. The antipsychotic and side effects were rated according to the CPRS and the Simpson and Angus scale. CPZ concentrations were measured by a mass fragmentographic method. Treatment with CPZ resulted in a significant reduction of morbidity scores, without any clear dose relation. The final outcome was more favourable in women than in men. Extrapyramidal side effects but not somnolence were positively dose related. The antipsychotic effects tended to be positively related to the dose of CPZ in mg/kg as well as the CPZ concentrations in plasma and CSF. The greatest number of significant correlations between the CPZ concentration in CSF and the morbidity scores were seen after 2 weeks of treatment. The results indicated marked clinical improvement with CPZ concentrations above 1 ng/ml in CSF and 40 ng/ml in plasma. After 4 weeks of treatment the correlations between the CPZ concentrations and the clinical improvement were still positive but the coefficients were lower than at 2 weeks and only occasionaly significant. Extrapyramidal symptoms were significantly related to the CPZ concentrations in plasma and CSF. Somnolence was significantly related to the CPZ concentrations in CSF.

Effect of chlorpromazine treatment on prolactin levels in cerebrospinal fluid and plasma of psychotic patients.

In psychotic patients, levels of prolactin in cerebrospinal fluid (CSF) and plasma were determined by radioimmunoassay before and after 2 and 4 weeks of treatment with chlorpromazine (CPZ). CPZ was given in one of three randomly selected fixed doses: 200, 400 or 600 mg per day. Before treatment, low levels of immunoreactive prolactin-like material (PRL) were found in the CSF of most patients. The concentration in CSF was about 20% of the plasma level. In CSF but not in plasma, the pre-treatment level of PRL was significantly higher in women than in men. During CPZ treatment, the PRL levels in CSF as well as in plasma were significantly elevated in both sexes after 2 as well as 4 weeks. The elevation was significantly greater in women, and was similar at the two time intervals studied. There was a significantly positive relationship between the dose of CPZ and the PRL elevation in both body fluids in both men and women. Before treatment no significant correlation between the PRL levels in CSF and plasma in either sex could be observed. During treatment, there was a significant correlation between the change in PRL levels in CSF and plasma in both men and women. CPZ treatment did not increase the levels of total protein, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) or oestradiol-(17-beta) in either the CSF or the plasma.

Effect of chlorpromazine treatment on monoamine metabolite levels in cerebrospinal fluid of psychotic patients.

Levels of HVA, MOPEG and 5-HIAA in cerebrospinal fluid (CSF) from psychotic men and women with a schizophrenic symptomatology were measured by mass fragmentography. Measurements were made before, 2 and 4 weeks after treatment with chlorpromazine (CPZ) which was given randomly in doses of 200, 400 or 600 mg per day. Before treatment there were positive correlations between the levels of HVA and 5-HIAA in both sexes. During CPZ treatment HVA was significantly elevated, whereas MOPEG and 5-HIAA were reduced. There was a tendency towards tolerance to CPZ's effect on HVA during treatment but a significant effect persisted after 4 weeks. No indication of tolerance to the effects on MOPEG or 5-hiaa was found. There were the same tendencies for the elevations of the HVA/MOPEG and HVA/5-HIAA ratios. The changes in HVA, MOPEG, 5-HIAA, HVA/MOPEG and HVA/5-HIAA were related to dose of CPZ in men but not in women. The bidirectional change of the different metabolites in CSF during CPZ treatment excluses a general and non-specific mechanism for the metabolite changes. The HVA elevation is in accordance with previous results in animals and man, and is presumably related to blockade of central dopamine receptors. Possible mechanisms for the effects on MOPEG and 5-HIAA are discussed.

Mass fragmentographic analysis of clomipramine and its mono-demethylated metabolite in human plasma.

A mass fragmentographic method for the quantification of clomipramine (CIM) and monodemethyl-clomipramine (DCIM) in human plasma was developed. The deuterium labelled analogues of the compounds were used as internal standards. The sensitivity of the method allows the determination of CIM and DCIM in plasma after oral doses with a standard deviation less than 7% at concentrations of 25 ng/ml. The method was applied to the analysis of drug concentrations in plasma of clomipramine treated healthy volunteers and depressed patients. After acute treatment the level of DCIM in plasma was low as compared to chronical treatment.

The effect of lithium treatment on manic symptoms and levels of monoamine metabolites in cerebrospinal fluid of manic depressive patients.

Clinical effects, levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) and lithium levels in serum were examined in 13 manic depressive patients acutely admitted because of a manic or hypomanic episode. Patients were examined before and 12 days after the beginning of lithium treatment. Manic scores were significantly reduced during treatment. The levels of 5-HIAA as well as HVA increased significantly during treatment. The HVA to 5-HIAA ratio was significantly reduced, indicating a more pronounced change in 5-HIAA than in HVA. The 5-HIAA and HVA levels before as well as after 12 days of treatment were significantly correlated. No significant correlation was found between manic scores and monoamine metabolites in CSF or between lithium level in serum and reduction of manic scores or elevation of monoamine metabolites in CSF in the relative small number of patients studied.