Finn Bengtsson

Citalopram in Premenstrual Dysphoria: Is Intermittent Treatment During Luteal Phases More Effective Than Continuous Medication Throughout the Menstrual Cycle?

In a double-blind trial, the selective serotonin reuptake inhibitor citalopram was administered to women with severe irritability and/or depressed mood in the luteal but not in the follicular phase of the menstrual cycle (premenstrual dysphoria). Treatment continued for three consecutive menstrual cycles. One group (N = 17 completers) was administered citalopram continuously at a constant dosage (20+/-10 mg/day) throughout the menstrual cycle. A second group (N = 17) also received citalopram continuously throughout the cycle, but at a lower dosage in the follicular phases (5 mg/day) than in the luteal phases (20+/-10 mg/day) (semi-intermittent treatment). A third group (N = 18) received citalopram (20+/-10 mg/day) in the luteal phase only and placebo during the follicular phase (intermittent treatment). A fourth group (N = 17) received placebo throughout the cycles. The side effects of active treatment were generally mild and transient. Intermittent administration of citalopram was clearly more effective than placebo with respect to both reduction in self-rated irritability and self-rated global improvement; it is of interest that intermittent treatment with citalopram also seemed more effective than continuous or semi-intermittent administration of the drug.

Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients

Objective: This study was initiated in order to describe and evaluate the effects of a therapeutic drug monitoring (TDM) routine of selective serotonin reuptake inhibitors (SSRIs) on treatment strategies and drug costs in depressed elderly patients.

Preservation of brain temperature during ischemia in rats.

Our objectives were to study the loss of heat from ischemic brain and to devise a method of maintaining brain temperature. Reversible forebrain ischemia was induced by carotid clamping and exsanguination in 30 anesthetized and artificially ventilated rats. Rectal, skull, and brain temperatures were measured, confirming previous findings that brain temperature falls by 4-5 degrees C during 15 minutes of ischemia unless measures are taken to maintain head temperature by external heating. Temperature gradients developed within the ischemic brain, superficial tissues being cooler than deep ones. These temperature gradients were reversed when skull temperature was maintained at core body (rectal) temperature by external heating. With rectal and skull temperatures maintained at 38 degrees, 37 degrees, 35 degrees, or 33 degrees C, brain temperatures nonetheless decreased by approximately 1 degree C during ischemia. This decrease in brain temperature could be prevented by placing the rat in a Plexiglas box with circulating air at temperatures close to that of the body core and a relative humidity of approximately 100%. We also found that, unless special precautions are taken, a temperature gradient develops between the brain and body core during recirculation.

Sertraline Versus Paroxetine in Major Depression: Clinical Outcome After Six Months of Continuous Therapy

reuptake inhibitors (SSRIs) during continuation therapy. This investigation reports the differential effect of 6 months of treatment with sertraline versus paroxetine for symptoms of depression, quality of life, and personality outcomes. Outpatients with unipolar major depression (DSM-III-R) were randomly assigned to receive 24 weeks of double-blind treatment with flexible doses of paroxetine (20-40 mg) or sertraline (50-150 mg). Assessments included the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale, the Battelle Quality of Life Questionnaire, and the Structured Clinical Interview for DSM-III-R Personality Disorders screen questionnaire. One hundred seventy-six patients (mean age, 43 years; 64% female; baseline MADRS, 30.3) were treated with sertraline and 177 patients (mean age, 42 years; 71% female; MADRS, 30.7) with paroxetine. Antidepressant efficacy during continuation therapy was sustained, with only 2% of patients receiving sertraline and 9% of patients receiving paroxetine suffering a relapse. Continuation therapy resulted in a substantial conversion of responders during short-term treatment to full remission: remitter rates increased from 52% to 80% for sertraline and from 57% to 74% for paroxetine. The improvements in quality of life were related to a reduced depression score. SSRI treatment had significant beneficial effects on both categorical and dimensional measures of personality. A logistic regression analysis identified early response (25% reduction in MADRS scores at week 2) as the most important predictor of treatment response, whereas high severity, chronicity, and poor baseline quality of life had no effect. Both treatments were well-tolerated, with sertraline having a somewhat lower side effect profile. Sertraline and paroxetine demonstrated comparable efficacy during short-term and continuation therapy. Treatment was associated with significant improvement in quality of life and with reductions in axis II personality psychopathology.

Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting

Olanzapine (Zyprexa®) was approved for general prescription in Sweden in November 1996, and an HPLC-based therapeutic drug monitoring (TDM) routine for serum olanzapine (OLA) and its major metabolite, N-demethylolanzapine (DMO) was established in February 1997. During 1997 to 1999, a total of 753 TDM requests for a total of 545 Swedish patients was analyzed. Additional patient information on certain clinical variables was collected on specifically designed TDM request forms. After the exclusion process, samples from 194 patients were found to be eligible for further scrutiny. The concentration-to-dose (C/D) ratio for OLA varied 25-fold and that of DMO 22-fold. Women had a higher (P < 0.01) median C/D ratio for OLA than men (median, 7.2 nmol/L/mg vs 5.2 nmol/L/mg). Nonsmokers had a higher (P < 0.001) C/D ratio for OLA than smokers (median, 9.2 nmol/L/mg vs 4.0 nmol/L/mg). Smokers got higher prescribed (P < 0.05) doses of OLA than nonsmokers did. In the group with reported side effects, the median serum OLA concentration was 22% higher (P < 0.05) than in the group without side effects. Patients co-medicated with carbamazepine had a 71% lower median C/D ratio for OLA than patients on OLA monotherapy. The present TDM-based follow-up suggests that the influence of gender, smoking habits, and certain drug interactions may need to be considered for optimal dosage of OLA. TDM may be used for this purpose more readily in the future.

Portacaval shunt in the rat: Selective alterations in behavior and brain serotonin

Portacaval shunted (PCS) rats and sham-operated controls were investigated for spontaneous activity, exploration, somatosensory reactivity, swim latencies in a water maze, motor coordination, and passive avoidance 2 to 3 weeks after operation. The rats were subsequently decapitated and indole metabolism was investigated in different brain regions. The results showed that shunted rats were impaired in both open field tests (spontaneous activity and exploration) and in somatosensory reactivity (latency to respond, maximal response and integrated response). Results from motor coordination tasks and learning and memory tests (water maze and passive avoidance) did not demonstrate differences between the groups. There was an increased brain indolamine metabolism in PCS compared to sham-operated rats. No correlation between the behavioral impairment and the altered indolamine metabolism could be demonstrated with multiple correlation analysis.

Brain monoamine metabolism and behavior in portacaval-shunted rats

Animals with a portacaval shunt exhibit several biochemical abnormalities in plasma and brain similar to patients with portal-systemic encephalopathy, i.e., hyperammonemia, amino acid imbalance, and neurotransmitter disturbances. We investigated behavior and brain monoamine metabolism in operated, sham-operated, and nonoperated rats 1 day and 2, 4, and 6 weeks after operation. In order to quantitate the turnover in the brain indoleamine and catecholamine systems, 5-hydroxytryptophan (5-HTP) and dihydroxyphenylalanine were measured after decarboxylase inhibition with NSD 1015. The brains were dissected into five regions. All rats with the shunt had high plasma ammonia concentrations. Behavioral tests revealed a reduction in spontaneous locomotion 2, 4, and 6 weeks after portacaval shunt and reduced exploratory behavior compared with control rats. These changes coincided with profound alterations of the indoleaminergic system. As early as 1 day after surgery, rats with the shunt showed a marked increase in the accumulation of 5-HTP in all brain regions, indicating an enhanced tryptophan hydroxylase activity. The changes in indoleamine synthesis were most profound in the cortex and the midbrain. Only minor alterations of the catecholaminergic system could be detected. The alterations in behavior and indoleamine neurotransmitter metabolism may be pathophysiologically interrelated and may serve as the basis for experimental studies of portal-systemic encephalopathy.

Could discontinuing smoking be hazardous for patients administered clozapine medication? A case report

A 35-year-old man with schizophrenia was successfully treated with clozapine at a daily oral dose of 700-725 mg for more than 7 consecutive years. Two weeks after abrupt cessation of chronic heavy cigarette smoking, he suddenly developed tonic clonic seizures followed by stupor and coma. After 2 days of intensive care, the patient recovered completely but could not recall the episode. Clozapine therapy was reinstituted and could be carried out successfully at 425 mg daily, i.e., at an approximately 40% reduction of the daily dose before he stopped smoking. The sudden cessation of smoking most likely caused a rise in plasma concentrations of clozapine and/or clozapine metabolites resulting in the seizure episode. A likely mechanism is that the heavy smoking had induced cytochrome P450-1A2, the main enzyme involved in the metabolism of clozapine.

Therapeutic drug monitoring of sertraline: variability factors as displayed in a clinical setting.

This report describes sertraline pharmacokinetics derived from routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method with ultraviolet detection was established for routine sertraline TDM, and 924 analyses were performed from April 1995 to May 1997. Extensive predefined inclusion/exclusion criteria were applied to increase the validity of scientifically evaluated data. Subsequently, 605 samples (65.5%) were excluded. The remaining 319 samples from 319 patients, representative of steady state trough specimens and accompanied by essential clinical information provided on request forms, were scrutinized. A pronounced interindividual variability was observed. Smokers had significantly lower concentration-to-dose (C/D) mean ratios of serum sertraline (s-sert) and its main metabolite desmethylsertraline (s-dsert) than nonsmokers. Higher s-sert and s-dsert C/D mean ratios were found in elderly patients than in adults aged less than 65 years. In a subset of 20 patients in whom repeated TDM analyses were performed, observed intraindividual sertraline TDM outcome variability was low. The results highlight sertraline TDM as a tool for individual dose optimization and evaluation of patient drug compliance as well as drug-drug interactions.

Therapeutic drug monitoring of racemic citalopram : a 5-year experience in Sweden, 1992-1997

Racemic citalopram (CIT) was introduced in Sweden in 1992 for management of major depression. During a 5-year period, 1992 to 1997, serum samples of CIT and desmethylcitalopram (DCIT) were collected for therapeutic drug monitoring (TDM) from patients from all over Sweden. These samples were accompanied by clinical information on a specially designed TDM request form. They represented men and women of various ages (11–94 years) usually on multiple concomitant medications and treated in a naturalistic setting. The TDM samples eligible for evaluation (n = 749), all trough values at steady state, were studied with respect to inter- and intraindividual pharmacokinetic variability. Extensive, interindividual serum concentration variability was seen on all dose levels. For dose-corrected concentrations (C/D) and for clearance (Cl) we found the coefficient of variation (CV) to be approximately 55% for all variables (C/D CIT, C/D DCIT, the ratio DCIT to CIT, and for Cl CIT). The intraindividual variations over time for the same parameters were 30% to 35%. On a population level, signs of a possible saturation of CYP2D6 associated with increasing DCIT-to-CIT ratios with increasing daily doses was observed. Age and gender affected the pharmacokinetics of CIT and DCIT. Women showed significantly higher C/D CIT and C/D DCIT and lower Cl CIT values compared with men, and patients aged more than 65 years had higher C/D CIT and C/D DCIT and lower Cl CIT values compared with younger patients. Finally, concomitant medication affected the outcome of serum concentrations by a general increase in C/D CIT and C/D DCIT but without alteration in the DCIT-to-CIT ratio. Thus, this tendency of changes in the CIT disposition when multiple drugs are used (and multiple diseases are prevailing?) seems more general in character than specific for a certain drug or type of drugs.