Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study.

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.     

Carbamazepine overdose: a prospective study of serum levels and toxicity

A cooperative prospective study of consecutive cases of carbamazepine overdose was conducted to determine if serum levels were predictive of toxicity and if risk factors such as age, chronic exposure, or previous disorder or cardiovascular disease could be used as prognostic indicators. Seventy-three consecutive cases were collected from two regional certified poison control centers from January 1989 to August 1989. There were 25 exposures in children less than 6 yrs., 11 exposures in adolescents, and 37 exposures in adults. Ten adult cases and one adolescent case were excluded from the study due to the presence of coingestants or inadequate information. Peak measured serum levels ranged from 0.3 to 56 mcg/ml. Using the presence of coma, seizure activity or respiratory depression requiring mechanical ventilation as measures of toxicity, we found poor correlation between rising serum levels of carbamazepine and toxicity. Increased serum levels of carbamazepine did appear to correlate with increased hospital stay, but not with ICU stay. History of a seizure disorder appears to pose increased risk of a seizure in carbamazepine overdose. In this series chronic exposure to carbamazepine did not appear to increase the risk of coma or respiratory depression for a given toxic serum level and may add some protective effect. Serum levels below 40 mcg/ml do not appear to accurately predict the severity of toxicity. Cardiac conduction defects were rare (one child). Anticholinergic findings, as evidence by decreased bowel motility and sinus tachycardia were common. Previous cardiovascular disease and age did not appear to be important prognostic indicators.     

Delirium tremens: a prospective long-term follow-up study

A follow-up by health insurance records of 716 male hospital-treated alcoholics revealed a tendency to a more favorable long-term adjustment in patients with delirium tremens at first admission compared with others. Standardized ratings at first admission indicated that the delirium patients had lower frequencies of depressive symptomatology, personality disturbance and social complications. Slight cerebral impairment at first admission was more frequent in the delirium patients, perhaps indicating a more severe abuse. In a subsample of 105 personally followed-up patients it was found that subjects with delirium later during the course of their illness were characterized by a lower level of social stability at first admission, compared with those with an initial delirium or with no history of delirium tremens. Contrary to initial delirium, later delirium was related to an unfavorable course. Six subjects with a history of delirium tremens were found to have taken up social drinking. Patterns and processes of improvement were found to be related more to background characteristics in terms of personality disturbance and social stability than to the severity of withdrawal symptoms.     

Comparative effectiveness of azathioprine in Crohn's disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients

Background The long‐term efficiacy for thiopurinic drugs in Crohn’s disease (CD), and particularly in ulcerative colitis (UC), has been insufficiently studied. Aim To evaluate prospectively and compare the long‐term effectiveness of azathioprine (AZA) in CD and UC. Methods Three hundred and ninety‐four AZA treated patients were included consecutively included. Truelove‐modified index and CDAI were used to assess effectiveness. Hospitalizations and surgical procedures were recorded. Results Two hundred and thirty‐eight patients with CD and 156 with UC received AZA for a median of 38 months. Effectiveness: Partial response/remission was achieved in 34%/49% of CD patients and in 47%/42% of UC (nonstatistically significant differences). Steroid treatment: Prior to AZA, 49% of CD patients were receiving steroids, whereas only 8% needed steroids after therapy (P < 0.001). Corresponding figures in UC patients were 39% vs. 9% (P < 0.001). Hospitalizations: Prior to AZA, the rate of hospitalizations in CD was 0.190 per‐patient‐year, while after treatment, it decreased to 0.099 (P < 0.001). Corresponding hospitalization rates in UC were 0.108 vs. 0.038 (P < 0.001). Surgery: The rate of surgery in CD prior/after AZA was 0.038/0.011 per‐patient‐year (P < 0.001). The number of surgical interventions in UC prior/after AZA treatment was 26/0 (the rate per‐patient‐year was 0.018/0) (P < 0.001). Conclusions Our results confirm the effectiveness of AZA in inflammatory bowel disease, not only in the short term but also in the long term, resulting in a steroid sparing effect and in both a reduction in the number of hospitalizations and surgical procedures. AZA is similarly effective for both CD and UC patients.     

Carbamazepine prophylaxis in refractory affective disorders: a focus on long-term follow-up

Twenty-four patients with refractory affective disorders who were taking carbamazepine were followed in an open-label fashion for an average of 4 years. Carbamazepine, usually in combination with lithium and other previously ineffective medications, reduced the number and severity of manic and depressive episodes. An overall illness index of morbidity (duration x severity) decreased 72% in the first year and 66% in the second year of carbamazepine treatment. One-half of the patients (N = 11) who were followed for more than 2 years showed a pattern of continued improvement (stable); the other half showed loss of prophylaxis (escape). Those showing the escape pattern had a more rapidly deteriorating course of illness in the 4 years before the study than those showing the stable improvement. Clinical and mechanistic implications of these findings are discussed, including the phenomenon of contingent tolerance as a possible explanation for the emergence of loss of efficacy in a subgroup of patients.     

Carbamazepine in rapid cycling bipolar affective disorder

Eighteen patients with rapid cycling bipolar affective disorder were recruited for an open trial of carbamazepine. Of these patients all but 2 had been resistant to lithium prophylaxis. Twelve of the patients were able to complete at least 6 months on carbamazepine. Of these 12 patients, 2 had a complete remission of their affective disorders on carbamazepine alone, 2 completely responded to combined lithium and carbamazepine treatment, 3 had a slight beneficial effect from the drug, and for the other 5 patients carbamazepine was of no therapeutic benefit. This suggests that, while carbamazepine is effective for some rapid cycling patients, for the majority alternative treatment strategies are still required.     

Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study

Rationale The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients. Objectives To our knowledge, no longitudinal volumetric study has been performed in patients with BD, which would allow for an examination of whether lithium therapy used to treat BD can exert a long-term effect on hippocampal volume. Materials and methods We examined the effects of lithium on hippocampal volumes and recollective memory performance over a period of 2 to 4 years in 12 patients with BD who had never received pharmacotherapy before lithium initiation. Results We found bilateral increases in volume of the hippocampus over time. We also found some evidence of improvement in verbal memory performance over the 4-year measurement period as assessed by the California Verbal Learning Test. Conclusions Consistent with preclinical literature supporting the neuroprotective effects of lithium, long-term treatment is associated with preservation of recollective memory function and increased hippocampal size in vivo.     

Effect of digoxin noncompliance on hospitalization and mortality in patients with heart failure in long-term therapy: a prospective cohort study

BACKGROUND: As outpatients with long-term chronic illness often show a high incidence of medication noncompliance, we investigated the influence of digoxin noncompliance on hospitalization, left ventricular ejection fraction, and mortality in outpatients in long-term therapy having congestive heart failure with tachycardia at a rate over 100 beats/min before starting digoxin therapy, but abnormal sinus rhythm. METHODS: Before starting this study, the digoxin compliance/noncompliance of patients was determined by measuring the serum digoxin concentration (SDC). SDC was determined once a month, followed for six consecutive months, and patients were defined as noncompliant if their SDC was zero (0.0 ng/ml) on at least three consecutive occasions. According to SDC data, 218 patients were assigned to the compliant group and 213 patients were assigned to the noncompliant group. All 431 patients received diuretics, angiotensin converting-enzyme inhibitors, or nitrates as well as conventional therapy with digoxin throughout the trial. The duration of follow-up was 72 months. FINDINGS: After 72 months of follow-up, the digoxin noncompliant patients showed significant increases in the number and duration of hospitalizations compared with the compliant patients. The digoxin noncompliant patients had a marked decrease in the left ventricular ejection fraction from 49.1% to 41.8%. The cumulative rate of mortality from any cause in noncompliant patients was twofold higher (15.0%) than in compliant patients (7.8%; risk ratio when noncompliant was compared with compliant: 1.95; 95% confidence interval 1.11, 3.45; P = 0.029) at the 72-month follow-up. The higher mortality in digoxin noncompliant patients was exclusively attributed to worsening heart failure rather than other cardiac and noncardiac causes (risk ratio 2.13; 95% confidence interval 1.12, 4.07; P = 0.033). In addition, multiple regression analyses demonstrated that patient noncompliance as well as lower left ventricular ejection fraction at baseline were significantly involved in increased mortality. CONCLUSION: These results indicate that digoxin noncompliance, at least in part, increases the rate of both hospitalization and mortality due to worsening heart failure in outpatients who have congestive heart failure with tachycardia in long-term therapy.     

Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study

Treatment of aggression in schizophrenic patients is a major challenge. We sought to examine the efficacy of augmentation of antipsychotic treatment with pindolol in the amelioration of aggression. Thirty male inpatients meeting DSM-IV criteria for schizophrenia, aged 20-65 years involved in four or more aggressive incidents in the two previous months, were enrolled in a double-blind crossover study. Aggression was evaluated per incident, with the Overt Aggression Scale (OAS). Positive and Negative Syndrome Scale (PANSS) was administered at baseline, crossover and at endpoint. Patients received either pindolol or placebo augmentation 5 mg x three times a day until crossover, then switched. No significant differences were found in the PANSS scores between the placebo and pindolol treatments. OAS scores were significantly reduced for number of aggressive incidents towards objects and other persons during pindolol treatment (0.59 versus 1.46, F = 6.09, P < 0.02; 1.96 versus 3.23, F = 4.17, P < 0.05, respectively). Similar results were obtained for severity of incidents (0.89 versus 3.58, F = 19.42, P < 0.0001; 2.89 versus 6.85, F = 10.11, P < 0.004, respectively). Pindolol, with its dual beta and 5-HT1A blocking effect ameliorated both number and severity of aggressive acts. Influence on severity may be associated with a 5-HT1A antagonistic effect.     

An open prospective study of zonisamide in acute bipolar depression

OBJECTIVE: To examine the effectiveness and safety of zonisamide in the treatment of acute bipolar depression. METHODS: An open-label, prospective, nonrandomized, 8-week study conducted in bipolar outpatients (type I, type II, or not otherwise specified) with depressive symptoms. No patient was manic or mixed at study entry. Previous treatments were continued unchanged, but no new treatments were allowed. Montgomery Asberg Depression Rating Scale and the Mania Rating Scale from the Schedule of Affective Disorders and Schizophrenia-Change Version were used. RESULTS: Twenty patients (10 men, 10 women) with bipolar disorder (17 type I, 2 type II, 1 NOS), aged 38.1 +/- 8.81 years, received zonisamide at mean dose of 222.5 +/- 85.1 mg/d. Mean Montgomery Asberg Depression Rating Scale scores improved significantly from baseline to endpoint (mean difference = -8.4, 95% confidence interval [4.1, 12.6], P = 0.001). Ten patients (50%) terminated early due to adverse effects, mostly side effects including nausea/vomiting, cognitive impairment, and sedation. One patient experienced increased suicidal ideation, and one patient experienced hypomania. CONCLUSIONS: This study suggests improvement of depressive symptoms in this sample with 8 weeks of open-label zonisamide treatment.     

Carbamazepine: a bioequivalence study and limited sampling modeling

OBJECTIVES: To assess the bioequivalence of 2 formulations of carbamazepine and to develop and validate limited sampling strategy (LSS) models for estimating the area under the plasma concentration-time curve (AUC0-infinity) and the peak plasma concentration (Cmax) of carbamazepine. METHODS: Twenty-four (12 men, 12 women) healthy volunteers received single oral doses (400 mg) of carbamazepine, as reference and test conventional-release formulations, in a standard 2-sequence, 2-period crossover design. Bioequivalence assessment was based on the individual ratios of log-transformed values of AUC0-infinity and Cmax LSS modeling was developed in a training set of 12 randomly assigned volunteers and was validated on the other 12 subjects (validation set). RESULTS: Carbamazepine AUC0-infinity and Cmax can be accurately predicted (R2 = 0.89 - 0.95, precision = 2.6 - 7.2%) by single-point (72 h) and 2-point LSS models (6, 32 h), respectively. Bioequivalence assessments based on LSS-derived AUC0-infinity and Cmax provided results similar to those obtained using all the concentration-in-plasma data points, and indicated that the 2 formulations are bioequivalent. CONCLUSION: One-and 2-point LSS models provided accurate estimates of carbamazepine's AUC0-infinity and Cmax, and allowed correct assessment of bioequivalence between the formulations studied.     

Effects of lithium on platelet membrane phosphoinositides in bipolar disorder patients: a pilot study

Rationale: In vitro and in vivo animal studies suggest that the intracellular phosphatidylinositol (PI) pathway is an important target for the effects of lithium. Objectives: We conducted a preliminary study to examine the in vivo effects of lithium treatment on platelet membrane phosphoinositides in bipolar disorder subjects, in an attempt to examine further the hypothesis that lithium has significant in vivo effects on the PI pathway in these patients. Methods: We quantitated PI, phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP₂) in platelet membranes of seven subjects (five male, two female; mean age= 27.9±5.7 years), initially while they were unmedicated, and a second time after at least 21 days of lithium treatment (mean±SD=28.7±7.1 days). Results: The mean±SD values for PI were 5.63±2.25% and 5.21±1.06%; for PIP 0.68±0.20% and 0.55±0.11%; and for PIP₂ 0.60±0.21% and 0.38±0.15%, before and after lithium treatment, respectively. The decrease in PIP₂ values after lithium treatment was statistically significant (Wilcoxon signed ranks test, Z=–2.37, P=0.02). Conclusion: This longitudinal study suggests that therapeutic doses of lithium significantly decrease platelet membrane PIP₂ levels in vivo in bipolar disorder subjects, which may be related to lithium’s mechanism of action in bipolar disorder. Received: 18 March 1999 / Final version: 5 November 1999     

Interferon-alpha therapy in HBeAg-negative chronic hepatitis B: a long-term prospective study from north-western Greece

AIMS: To determine the long-term response to interferon-alpha therapy in patients with hepatitis B e antigen-negative chronic hepatitis B, and the factors independently associated with response and survival. METHODS: Sixty-three patients with documented hepatitis B e antigen-negative chronic hepatitis B treated with interferon-alpha for a year were followed-up for a period of 6 years. RESULTS: Sustained biochemical and virological response was seen in 34.91% and 33.33% of patients at 6 and 12 months of follow-up, respectively, and histological improvement in 54.5% of sustained responders compared with non-responders (7.1%, P = 0.004, chi-squared test), at 6 months of follow-up. Multivariate analysis showed that patients with hepatitis B virus-DNA levels at 6 months of treatment <10,000 copies/mL had a low probability of relapse, compared with those with levels >10 000 copies/mL (P = 0.032). Age (>65 years) and hepatitis B virus-DNA level at 6 months of treatment (>10,000 copies/mL) were the independent factors for disease progression and survival (P = 0.041 and P = 0.044 respectively). At 6 years, a sustained response was still present in 19.04% of patients and 4.8% of them had developed anti-HBs. CONCLUSION: Hepatitis B virus-DNA monitoring by quantitative polymerase chain reaction at 6 months of treatment may allow for early prediction of response to interferon-alpha, and may serve as an indicator of disease progression in the future.