Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients.

The bicyclic compound Z-1-(4-bromophenyl)-1-(3-pyridyl)-3-dimethylaminopropen (zimelidine) has a pronounced inhibitory effect on neuronal 5-hydroxytryptamine (5-HT) uptake in animals. Zimelidine was given to 6 depressed patients in doses ranging between 25 and 150 mg twice daily for about 3 wk. To get an objective assessment of its pharmacologic effects, the following variables were monitored: (1) plasma levels of parent compound and its desmethylated metabolite; (2) the 5-HT and norepinephrine (NE) uptake inhibiting activity in vitro of plasma drawn from the patients; and (3) the concentrations of the main metabolites of serotonin (5-HT), tryptamine, NE, and dopamine in cerebrospinal fluid (CSF), i.e., 5-hydroxyindoleacetic acid (5-HIAA), indoleacetic acid (IAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and homovanillic acid (HVA), respectively. Plasma from the patients markedly inhibited 5-HT uptake compared to NE uptake. The inhibitory effect of 5-HT uptake and the plasma concentration of the desmethylated metabolite correlated significantly. The 5-HIAA levels in CSF decreased markedly in 4 patients while the IAA levels increased. The levels of HMPG also decreased significantly, but less so than the 5-HIAA levels. The effects on HVA were inconsistent. Zimelidine appears to be a selective inhibitor of 5-HT uptake in central monoamine neurons and is therefore an interesting pharmacologic tool in future central nervous system (CNS) research.

Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chlorimipramine.

The effects of chlorimipramine on the concentrations of the main metabolites of serotonin (5-HT) norepinephrine (NE), and dopamine, i.e. 5-hydroxyindoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) and homovanillic acid (HVA), respectively, were studied in cerebrospinal fluid from 14 depressed patients, and related to the serotonin- and NE uptake inhibiting activity in vitro of plasma drawn from the patients. Chlorimipramine inhibited the uptake of both transmitter amines in all patients. During treatment, the levels of 5-HIAA and HMPG in cerebrospinal fluid (CSF) were significantly reduced. HVA levels were reduced in 6 patients and increased in 8 patients; there was no mean change. The decrease in 5-HIAA level in CSF was correlated to the uptake inhibition of 5-HT but there was no corresponding relationship between NE uptake and HMPG levels. The changes in HVA levels were also correlated to the uptake of 5-HT despite the absence of a unidirectional change of this metabolite.

Platelet monoamine oxidase activity and psychopathy.

Platelet monoamine oxidase (MAO) activity appears to be correlated to certain diagnostic subgroups and symptom patterns. A group of criminal offenders hospitalized for forensic psychiatric assessment were studied. Male nurses and construction workers were used as controls. Patients who were diagnosed as psychopaths according to the criteria of Cleckley had significantly lower platelet MAO activity than the control group of construction workers.

Pilot study of the adjunct utility of a computer-assisted Diagnostic Interview Schedule (C-DIS) in forensic psychiatric patients.

To assess the potential usefulness of a structured and computer-assisted diagnostic interview under field conditions, menu-driven interviews with 18 of 20 probands undergoing forensic psychiatric examination were scored into axis I DSM-III diagnoses, independent of the regularly derived ICD-9 diagnoses. The computer-assisted interview yielded more affective and anxiety disorders than routine clinical procedures, many of which were amenable to treatment. The computer interview was acceptable to the probands. Controlled studies are suggested to assess the benefits of computer-assisted diagnosis in addition to traditional diagnostic procedures in forensic psychiatric patients.

Biochemical effects of zimelidine in man.

The novel drug zimelidine 50--300 mg/day was administered to 12 depressed patients. After about 3 weeks plasma levels of the demethyl metabolite, norzimelidine, were almost thrice those of the parent drug. During incubation of slices of rat brain cortex in plasma from the treated patients, the neuronal uptake of serotonin and noradrenaline was 51.7 +/- 10.2 and 82.8 +/- 9.6%, respectively, of the control values. The uptake inhibition both of serotonin and noradrenaline was correlated with the plasma level of norzimelidine (r = 0.62 and 0.63, respectively). The major central metabolites of serotonin (5-HIAA) and noradrenaline (HMPG) in cerebrospinal fluid (CSF) decreased significantly (29 and 11%, respectively) during treatment with zimelidine. Although there was no mean change in the major dopamine metabolite (HVA) in CSF, the level during treatment (as percentage of the pretreatment level) was correlated with the effect of 5-HIAA in CSF. Thus, administration of zimelidine caused a relatively selective inhibition of serotonin uptake, mainly due to norzimelidine. A small but significant inhibition of noradrenaline uptake was also seen, but this effect was less pronounced than during chlorimipramine treatment. There was an effect on the dopaminergic system, probably secondary to the action of serotonergic neurons.

Pharmacokinetics of lofepramine in man: relationship to inhibition of noradrenaline uptake.

The pharmacokinetics of lofepramine, an imipramine analogue, have been studied by administering single oral doses to volunteers, determination of plasma levels of lofepramine and desemthylimipramine after ten days of oral administration to patients, and by relating plasma levels to the effect on uptake of noradrenaline by isolated rats irides and brain slices of plasma samples collected during treatment. The results indicate that lofepramine undergoes pronounced first pass elimination and that desmethylimipramine is a major metabolite of it. During steady-state conditions the plasma level of lofepramine fluctuates considerably between doses. A linear relation was found between inhibition of neuronal uptake of noradrenaline and the plasma concentration of desmethylimipramine. No effect was seen on the uptake of 5-hydroxytryptamine in brain slices incubated in patients' plasma which suggests that neither lofepramine nor its metabolites formed in vivo in man affect neuronal uptake is this amine. Lofepramine belongs to the group of tricyclic antidepressants which preferentially inhibit noradrenaline uptake.

Homicide, suicide and CSF 5-HIAA.

Concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenyl glycol (HMPG) in lumbar spinal fluid were measured by mass fragmentography in 16 men convicted for criminal homicide, 22 men who had attempted suicide, and 39 healthy male control subjects. Those men who had killed a sexual partner, and those who had attempted suicide, had lower levels of the serotonin metabolite, 5-HIAA in spinal fluid than the controls. It is suggested that low levels of 5-HIAA in spinal fluid reflect a disorder of serotonin turnover, which makes the individual more prone to acts of violence in states of emotional turmoil.