Chlorprothixene (CPX) and CPX sulphoxide were demonstrated in breast milk from two psychotic mothers taking 200 mg CPX daily. The milk concentrations of CPX were 120 to 260% greater than in plasma. ...The estimated amounts of drug administered in breast milk to one of the infants were 15 and 26 micrograms/day for CPX and CPX sulphoxide, respectively. Accordingly, the infant dose of the parent compound would be only 0.1% of the maternal dose/kg body weight. It is not likely that CPX or its metabolite would exert any immediate pharmacological effects in the nursing infant. However, the long term effect of low doses of neuroleptic drugs in the developing infants is not yet known.
The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. ...Administration of citalopram in the diet at a daily dose of 99 mumol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mumol/kg for 13 days and after oral bolus injection (49 mumol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.
The effects in rats of long-term administration of the potent, specific 5-HT uptake inhibitor citalopram have been investigated. Citalopram hydrobromide (MW = 405) was given in the diet, 99 or 25 ...mumol/kg daily, for 13 days or orally, 49 mumol/kg twice a day, for 14 days. High plasma and brain levels of citalopram were found during the treatment period, whereas negligible amounts were found 24 h after withdrawal. The 5-HT uptake mechanism in blood platelets was completely blocked, since levels of whole blood 5-HT during and shortly (2 days) after treatment were decreased by 75-90%. The drug load after the two highest doses in terms of plasma drug levels was the same as in depressed patients treated with citalopram. Receptor binding technique ex vivo was applied to different brain parts to measure receptor parameters for several neurotransmitters. All data were evaluated by Eadie- Hoffstee analysis. No changes were seen in Bmax and Kd for beta-receptors (3H-dihydroalprenolol) in frontal cortex, occipital + temporal cortex, whole cortex and limbic structures, 5-HT2 receptors (3H-spiroperidol) in frontal and whole cortex, alpha 1-receptors (3H-prazosin) in "rest of brain" and DA D-2 receptors (3H-spiroperidol) in corpus striatum and limbic structures. The uptake mechanism for 5-HT as well as the inhibitory effect of citalopram on this uptake remained unaffected in brain synaptosomes derived from control and from citalopram (99 mumol/kg)-treated rats. Thus long-term treatment with citalopram does not induce changes in neurotransmitter receptors as seen with most tricyclic as well as newer " atypical " antidepressants.
The kinetics of the antidepressant drug citalopram, a specific 5-HT uptake inhibitor, has been investigated in 11 elderly patients (age 73-90) and compared to previous data from younger patients and ...volunteers. The recorded steady state citalopram levels of 140-545 nM after a once-daily 20-mg dose were up to four times higher than expected from data in younger patients and volunteers. The biological half-life (1.5-3.75 days) and estimated systemic clearance (0.08-0.3 1/min) also differed from data in younger individuals (1.5 days and 0.4 1/min, respectively). Clearance values generally decreased with increasing age. Drug/metabolite ratios were higher in patients with the longest half-lives and lowest citalopram clearance, indicating reduced metabolic activity. No reduction in renal clearance was indicated by urine data, obtained for two of the patients. The study suggests that daily doses of 5-20 mg give approximately the same steady state plasma levels in elderly patients as doses of 40 mg in younger, and that this is due to reduced rates of metabolism in the elderly.
1. Citalopram is rapidly absorbed and slowly eliminated in man. The kinetics is linear and characterized by systemic and apparent oral clearance values of 0.4 l/min, a theoretical distribution volume ...of 14 l/kg and a half-life of 1 1/2 days. 2. The steady state plasma levels in 70 patients range from 95 to 720 nM at doses of 30 to 60 mg and agree well with predicted values. The mean level is 245 nM at the standard dose of 40 mg daily. 3. Inter-individual variation is 7-fold and independent of sex and age (21-65 years). The average intra-individual variation is about 15%. Estimates of apparent oral clearance vary from 0.15 to 1.02 l/min. 4. The average concentration ratio between citalopram and its demethylated metabolite is 2.7. The levels of di-demethylated metabolite are negligible.
In a double-blind trial, comprising 60 endogenously depressed patients, citalopram was compared with mianserin. Fifty-eight patients completed the 6-week trial period with ratings and side effect ...recordings at weeks 0, 1, 2, 4, and 6. Both drugs were administered as a single evening dose, 20-80 mg (most frequently 40 mg) for citalopram and 60-120 mg (most frequently 90 mg) for mianserin. CPRS (Subscale for Depression) total scores showed a highly significant reduction in both groups with a significant difference in favour of citalopram after 1 and 2 weeks. Based on the Global Evaluation of the Severity of Illness there were 18 complete and three partial responders on citalopram and 13 complete and four partial responders on mianserin. Six patients on citalopram and one patient on mianserin showed mild or moderate side effects, but no cardiovascular side effects were recorded. The authors conclude that citalopram is a safe antidepressant drug, presumably better than mianserin.
