Interaction between antidepressants andd-amphetamine on variable-interval performance

Four experiments were carried out investigating the interactions between some antidepressant drugs (imipramine, desipramine, fluvoxamine, trazodone (4 and 8 mg/kg) andd-amphetamine (0.1–3.2 mg/kg) on operant behaviour maintained under a variable-interval 80-s schedule of sucrose reinforcement; each experiment employed 12 rats.d-Amphetamine exerted a dose-related suppressant effect on response rate. Imipramine and desipramine given alone had no effect on response rate, whereas fluvoxamine (both doses) and the higher dose of trazodone produced significant increases in response rate. Pretreatment with imipramine, desipramine or fluvoxamine significantly potentiated the suppressant effect ofd-amphetamine on responding; pretreatment with trazodone had no significant effect. The potentiating effect of imipramine and desipramine may be related to their well known uptake blocking actions. The fact that fluvoxamine, a selective inhibitor of 5-hydroxytryptamine (5HT) uptake, also potentiated the effect ofd-amphetamine suggests that the suppressant effect ofd-amphetamine on operant behaviour may involve 5HT as well as catecholamine release. The lack of effect of trazodone may reflect its failure to influence uptake mechanisms. On the basis of a formal model couched in terms of Herrnstein's (1970) equation, it is suggested that imipramine, desipramine and fluvoxamine may have enhancedd-amphetamine's ability to reduce response capacity; it is suggested that the data do not provide evidence for an interaction between the antidepressants and the putative motivation-enhancing effect ofd-amphetamine.     

A double-blind,fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients

Antidepressant effects of mirtazapine and imipramine were compared in a randomized, double blind, fixed blood-level study with in-patients in a single centre. Patients with a DSM-III-R diagnosis of major depression and a Hamilton (17-item) score of ≥18 were selected. After a drug-free and a placebowashout period of 7 days in total, 107 patients still fulfilling the HRSD criterion of ≥18, started on active treatment. The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine. Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms. Eight patients dropped out and two were excluded from analyses because of non-compliance; 97 completed the study. According to the main response criterion (50% or more reduction on the HRSD score) 11/51 (21.6%) patients responded on mirtazapine and 23/46 (50%) on imipramine after 4 weeks’ treatment on the predefined blood level. Such a dramatic difference in efficacy between antidepressants has not often been reported before. The selection of (severely ill) in-patients, including those with suicidal or psychotic features, may have significance in this respect. Optimization of treatment with the reference drug imipramine through blood level control, exclusion of non-compliance for both drugs, exclusion of most concomitant medication and a low drop-out rate may also have contributed. It is concluded that imipramine is superior to mirtazapine in the patient population studied.     

Plasma levels of imipramine and desipramine in man after different routes of administration

Summary With the object of studying the kinetics of imipramine and desipramine five healthy volunteers received single intramuscular, oral and intravenous doses and multiple oral doses of imipramine hydrochloride on different occasions. Two of the volunteers also received single intramuscular and oral doses of desipramine hydrochloride.Great interindividual differences were noted in the plasma concentrations of imipramine and the formed desipramine after single doses of imipramine hydrochloride. In all subjects more desipramine was formed after oral than after parenteral administration of imipramine. The bioavailability of an orally administered dose of imipramine ranged between 29.5 and 54.7%. The concentration of imipramine was generally lower in the blood cells than in the plasma, unlike the concentration of desipramine which was considerably higher in the blood cells. The half-lives of imipramine ranged from 4.0–17.6 hrs (M=7.6±2.5) after single oral doses and between 9.2 and 20.2 hrs (M=14.0±1.9) after multiple oral doses. The half-lives of the formed desipramine ranged between 13.5 and 61.5 hrs (M=29.9±8.7) after multiple oral doses of imipramine hydrochloride. The observed mean steady-state plasma concentration after multiple oral doses of imipramine hydrochloride, 50 mg t.i.d., varied from 21.4–69.0 g/l (M=38.2±8.7) for imipramine and from 33.7–136.0 g/l (M=72.3±19.5) for desipramine. The great difference in the ability to form desipramine after oral and parenteral administration of imipramine hydrochloride may have therapeutic consequences as imipramine and desipramine have differing pharmacological properties.The results were presented to the Skandinavisk Selskab for Psykofarmakologi (Nagy and Johansson, 1974).     

Maintenance therapy with zuclopenthixol decanoate: associations between plasma concentrations,neurological side effects and CYP2D6 genotype

RATIONALE: Co-morbidity of mood and anxiety disorders is often ignored in pharmacotreatment outcome studies and this complicates the interpretation of treatment response. The clinical trials are usually based on single categories from the Diagnostic and Statistical Manual of Mental Disorders (DSM). OBJECTIVES: The present study is a first attempt to differentiate the responses to antidepressants using a design that differs from that used in previous clinical trials. To avoid bias due to co-morbidity, we included patients with any DSM-III-R diagnosis of mood or anxiety disorder for which antidepressant treatment was indicated. We also explored the role of the diagnosis at the first episode in the efficacy of the different antidepressants. METHODS: A total of 92 outpatients with a mood and/or anxiety disorder were randomly assigned to treatment with imipramine or fluvoxamine in a 6-week study. The diagnosis at the first episode--or primary diagnosis--was available for 78 patients, 40 with a primary depression and 38 with a primary anxiety disorder. RESULTS: Analyses using the MIXED procedure for repeated measures showed no general differences between treatment with imipramine and treatment with fluvoxamine. When the primary diagnoses were taken into consideration, differentiation occurred. Patients with primary depression showed better responses to imipramine than to fluvoxamine. The assumption that patients with primary anxiety disorder would respond better to fluvoxamine than imipramine was observed for only the Clinical Global Impression. CONCLUSIONS: The results suggest that the nature of the first illness episode may be more valuable than the DSM categories of mood or anxiety disorders, which may lend support to the concept of primary versus secondary depression for purposes of differentiating treatment responses. Given the exploratory nature of the study, however, replication of our finding is needed.     

Improving the provision of OTC medication information in community pharmacies in Poland

Background An informed or shared decision-making model is desirable to support the choice of over-the-counter (OTC) medications in pharmacies: it respects patient empowerment in self-medication. Such a model is achievable provided that pharmacists are a credible, competent information source open to patient needs. Objective To study the dependencies among selected factors that may influence the provision of OTC medication information. The study was conducted from the perspective of a community pharmacist. Method The study consisted of an auditorium survey with a self-administered questionnaire. We attempted to determine the relationships among three selected constructs: patient centredness (four items), competence (four items), and provision of OTC medication information (six items) as latent variables. We analysed hypothetical relationships among the observable variables and latent variables using structural equation modelling. Main outcome measure Selected factors that may influence the provision of OTC medication information. Results In all, 1496 pharmacists took part in the study. The model demonstrated adequate fit (χ² = 198.39, df = 64). The patient-centredness construct was demonstrated to have a strong direct positive impact on the provision of OTC medication information construct (β = 0.77, P < 0.05). Provision of OTC medication information was also shown to have a strong direct effect on the competence variable (β = 0.90, P < 0.05). Conclusion If a pharmacist is patient centred, there is a greater possibility that they will provide information about OTC medicines; that may influence the pharmacist’s feelings about their ability to cope with patient initiatives and enhance the pharmacist’s selfperceived competence.     

The benefits of a hospital based community services liaison pharmacist

Objective: to investigate the benefits of a community services liaison pharmacist in addressing medication misuse in elderly patients, which occur on both admission and discharge.Design: completion of a medication history for each patient on admission by the community liaison pharmacist. On discharge updated medication record sheets were faxed to the patient's GP and community pharmacy; a survey of GPs' and community pharmacists' opinions who were involved in the study was carried out.Subjects and setting: 109 patients over the age of 60 on 4 or more medications admitted by the medical admissions unit of Antrim Area Hospital.Main outcome measures: medication related problems; GP and community pharmacist opinions of the service.Results: of the 109 patients, 61% had an incomplete medication history on admission, 21% of patients who brought their own drugs were not dealt with appropriately in hospital and 33% of discharged patients had medicationrelated problems. The service was felt to be very useful by GPs (80%) and community pharmacists (100%). A reduction in readmission rate of 2.4% was seen in these patients compared to the average for this age group.Conclusion: the community services liaison pharmacist produced benefits in terms of patient medication management, reduced readmission rates and wastage of patients' own drugs. A more detailed oneyear study will now be carried out.     

Association study of a novel functional polymorphism of the serotonin transporter gene in bipolar disorder and suicidal behaviour

A serotonin transporter gene linked polymorphic region (5-HTTLPR) has been investigated in several genetic association studies, including studies of bipolar disorder (BD) and suicidality. The current study was designed to examine whether the new long (A/G) variant polymorphism of the 5-HTT gene may be associated with the suicide attempts in 305 families with at least one member having BD. No association with history of suicide attempt was found either in the multiallelic HTTLPR (LRS=0.15, df=2, P=0.92), or with the intron 2 variable number tandem repeat (VNTR) polymorphism (LRS=0.87 df=2 P=0.64). When we performed a haplotype analysis, we found no association between suicide attempt and haplotype distribution (LRS=1.84 df=4 P=0.76). These findings suggest that this new polymorphism in the 5-HTT gene may not influence suicidal behaviour in patients with bipolar disorder.     

Efficacy and safety of a medication dose reminder feature in a digital health offering with the use of sensor-enabled medicines

Objectives

Over one-half of patients with chronic diseases, such as hypertension and type 2 diabetes (DM), do not take medicines as prescribed. This study assessed the efficacy and safety of “seeing” versus “not seeing” medication dose reminders regarding medication adherence and risk for overdose.

Do asthma patients receive sufficient information to monitor their disease ? a nationwide survey in Finland

Objectives: The aim of this study was to assess to what extent the principles of asthma monitoring are implemented among Finnish asthma patients and if the patients have received sufficient information to adjust their medication according to asthma symptoms.Setting: All Finnish asthma patients receiving asthma medication from Finnish community pharmacies during two days in June 1998.Main outcome measures: The proportions of asthma patients who monitor their asthma status according to the national guidelines and have received specific instructions on how and when to adjust their asthma medication.Results: Eightysix per cent of the respondents (86%) monitored their asthma status on a method recommended by the national guidelines. They made Peak Expiratory Flow (PEF) measurements (39% of the respondents), they monitored their symptoms (34%) or both (13%). A smaller proportion of the respondents (58%) were instructed on adjusting their medication according to symptoms. The lowest rates for monitoring the asthma status was found among the elderly (65 years or more) and among those who reported that they had been on medication for longer than 5 years (17% and 13% of the subgroup populations, respectively). The lowest rates for having received specific instructions on adjusting their asthma medication according to symptoms were found among the elderly (36 %), among those who reported that they had been on asthma medication less than one year (44 %), and among males (54 %).Conclusions: Pharmacists and other health care professionals need to enhance their education activities and their cooperation in training asthma patients to monitor their disease, especially principles of adjusting medication according to symptoms. In this process, especially the training needs of the elderly patients and those who have been using asthma medicines for a long time need to be taken into account.     

Progesterone co-administration in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and taper outcome

Since recent research has suggested that the major metabolites of progesterone are barbiturate-like modulators of GABAergic function, we undertook a pilot study of the efficacy of micronized progesterone in attenuating withdrawal and facilitating discontinuation in benzodiazepine-dependent patients with a minimum of 1 year of continuous daily use. Forty-three patients taking a mean daily dose of 16.2 mg of diazepam (or its equivalent) were assigned, double-blind, to treatment with either placebo (n=13) or progesterone (n=30). Progesterone was titrated to a mean daily dose of 1983 mg, and was co-administered for 3 weeks, after which the benzodiazepine was tapered by 25% per week. Progesterone (or placebo) was then continued for 4 weeks before being discontinued. There was no progesterone versus placebo difference in the severity of taper withdrawal. Withdrawal checklist change scores were 17.3 for progesterone and 16.5 for placebo (F 0.63;df 2,31; n.s.), and the Hamilton rating scale for anxiety change scores were 7.8 for progesterone and 6.3 for placebo (F 0.22;df 2,30; n.s.). There was no difference in ability to remain drug-free at 12 weeks post-taper, with 57% of progesterone-treated patients, and 58% of placebo-treated patients having a successful outcome.     

Effect of antidepressant medication resistance on short-term response to electroconvulsive therapy

This prospective study assessed the influence of resistance to antidepressant pharmacotherapy on the short-term response to subsequent electroconvulsive therapy (ECT). Previous research has shown that patients with medication resistance were less likely to respond to ECT. This finding may be applicable to the population of depressed inpatients in The Netherlands, where ECT is often preceded by several medication trials. Eighty-five patients (61 female and 24 male patients) with DSM-IV criteria for depressive disorder, both with and without mood congruent psychotic features, were included for analysis. Medication resistance was rated with the Antidepressant Treatment History Form. Medication resistance was predefined in accordance with the previous research in this field. When a reduction of at least 50% on the 17-item version of the Hamilton Rating Scale for Depression (HRSD) between pre- and post-ECT is used as response criterion, medication-resistant patients were equally likely to respond to subsequent ECT (30/48 = 82.5%) than patients without medication resistance (30/37 = 81.1%). Even when post-ECT HRSD score < or = 7 was used (full remission), there was no significant difference between medication-resistant patients (21/48 = 43.8%) and patients without medication resistance (15/37 = 40.5%). When potential confounding variables were taken into account, these differences remain nonsignificant. In contrast to earlier research, medication resistance does not influence short-term response to subsequent ECT and it can still be of considerable efficacy.     

Comprehensive medication review recipients' opinions,actions, and information recall

Objectives

Assess patients' and caregivers' perceptions of comprehensive medication review (CMR) offers and when a CMR is needed, follow-up actions performed after the CMR, and recall of pharmacists' recommendations made during CMRs.

Treatment of Refractory Depression with High-Dose Thyroxine

In an open clinical trial we investigated whether addition of supraphysiological doses of thyroxine (T₄) to conventional antidepressant drugs has an antidepressant effect in therapy-resistant depressed patients. Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 ± 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 ± 72 μg/day. The patients’ scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 ± 4.7 prior to the addition of T₄ to 11.6 ± 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of ≱9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T₄ and followed up for a mean of 27.2 ± 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T₄ augmentation treatment, and one failed to profit from T₄ treatment during the follow-up period. Side effects were surprisingly mild, and no complications were observed at all. In conclusion, augmentation of conventional antidepressants with high-dose T₄ proved to have excellent antidepressant effects in approximately 50% of severely therapy-resistant depressed patients.     

Nicergoline in senile dementia of alzheimer type and multi-infarct dementia: a double-blind,placebo-controlled,clinical and EEG/ERP mapping study

In a double-blind, placebo-controlled study on the therapeutic efficacy and central effects of nicergoline, an ergot alkaloid with metabolic, antithrombotic and vasoactive action, 112 patients with mild to moderate dementia, diagnosed according to DSM IIIR criteria criteria (MMS 13-25), living in pensioners' homes, were included. Fifty-six were subdiagnosed as senile dementia of the Alzheimer type (SDAT), 56 as multi-infarct dementia (MID), based on computed tomography and Hachinski scores (49 SDAT, 7 MID). They received, after 2 weeks' run-in period (placebo), randomized for 8 weeks either 2 × 30 mg nicergoline (NIC) or 2 × 1 placebo (PLAC) orally. The four subgroups (SDAT/NIC, SDAT/PLAC, MID/NIC, MID/PLAC; 4 × 28 patients) were comparable in regard to age and sex. Only four, four, four and two patients of the respective groups did not finish the study for minor reasons. Confirmatory statistical analysis demonstrated in the target variable — the Clinical Global Impression (CGI) — a significant superiority of NIC over PLAC in both the SDAT and MID groups. Global improvement (CGI item 2) was seen in both nicergoline subgroups (3 and 3), while no changes occurred under placebo (4 and 4, respectively). The responder versus non-responder ratio was in the SDAT/NIC group 16/8, versus 8/16 in the SDAT/PLAC group (²=4.1,P=0.04); in the MID/NIC group 17/7, versus 7/19 in the MID/PLAC group (²=7.96,P<0.005). Furthermore, there was a significant improvement of the Mini-Mental State and the SCAG score in both the MID and SDAT group after 8 weeks of nicergoline, which was significantly superior to the minimal improvement or no change in placebo-treated SDAT and MID patients. EEG mapping demonstrated in NIC-treated SDAT and MID patients a significant decrease in delta and theta, increase in alpha 2 and beta activity and an acceleration of the centroid of the total power spectrum as compared with pretreatment, while opposite changes occurred in PLAC-treated SDAT and MID patients. The differences between PLAC and NIC reached the level of statistical significance. Event-related potential (ERP) recordings demonstrated a significantly shortened P300 latency under NIC treatment in both SDAT and MID patients, while there was a trend towards lengthening under PLAC. Thus, nicergoline improved vigilance and information processing at the neurophysiological level, which leads at the behavioural level to clinical improvement both in degenerative and vascular dementia.     

Effects of isradipine on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition

Rationale While the effects of d-amphetamine in increasing performance have been established, there is a paucity of information on the effects of methamphetamine on cognition in drug-naive subjects, and no published information on the effects of intravenous methamphetamine administration in dependent individuals. The dihydropyridine-class calcium channel antagonist, isradipine, has been posited as a putative treatment to prevent methamphetamine-associated hypertensive crisis and its sequelae. Yet, isradipines effects on cognitive performance in methamphetamine-dependent individuals are not known.Objective Since individuals whose dependence on methamphetamine is attributable to the need to enhance performance may be loath to take a cognition-impairing medication, even for the treatment of life-threatening hypertensive crisis, it would be important to determine isradipines effects on performance.Methods We therefore examined in a blinded, placebo-controlled, crossover design the cognitive effects of low and high doses of intravenous methamphetamine (15 mg and 30 mg, respectively) in both the presence and absence of isradipine.Results Intravenous d-methamphetamine produced dose-dependent increases in attention, concentration, and psychomotor performance. Isradipine, both with and without methamphetamine, had a modest effect to decrease attention.Conclusion Our results do not support the further testing of isradipine as a medication for improving the cognitive impairments that have been associated with chronic methamphetamine use.     

Fluvoxamine is a Potent Inhibitor of the Metabolism of Caffeine in vitro

Abstract: The selective serotonin re-uptake inhibitor, fluvoxamine, is a very potent inhibitor of CYP1A2, and accordingly causes pharmacokinetic interactions with drugs metabolised by CYP1A2, such as caffeine, theophylline, imipramine, tacrine and clozapine. Interaction between caffeine and fluvoxamine has been described in vivo, leading to lowering of total clearance of caffeine by 80% during fluvoxamine intake. The main purpose of the present study was to evaluate this interaction in vitro in human liver microsomes. A high-performance liquid chromatography method was developed in order to assay 1, 3-dimethylxanthine, 1, 7-dimethylxanthine, 3, 7-dimethylxanthine and 1, 3, 7-trimethyluric acid formed from caffeine by human liver microsomes. The limit of detection was 0.06 nmol · mg protein^?1 · hr^?1. As expected, fluvoxamine was a very potent inhibitor of the formation of the N-demethylated caffeine metabolites, displaying K_i values of 0.08–0.28 μM. The formation of 1, 7-dimethylxanthine was virtually abolished by 10 μM of fluvoxamine, indicating that the N3-demethylation of caffeine is almost exclusively catalysed by CYP1A2. The CYP3A4 inhibitors, ketoconazole and bromocriptine, inhibited 1, 3, 7-trimethyluric acid formation with K s of 0.75 μM and 5 μM, respectively, thus further supporting the involvement of CYP3A4 in the 8-hydroxylation of caffeine. The study shows that fluvoxamine, as expected, is a potent inhibitor of the metabolism of caffeine in vitro.     

Lack of correlation between fluvoxamine clearance and CYP1A2 activity as measured by systemic caffeine clearance

Objective: Evidence exists to suggest that fluvoxamine is metabolized by CYP1A2. The present study was undertaken in order to further elucidate the role of CYP1A2 in fluvoxamine disposition. Methods: Twelve healthy non-smoking male volunteers participated in this cross-over study. Six subjects received first fluvoxamine 50 mg as a single oral dose and, some weeks later, caffeine 200 mg as a single oral dose. The other six subjects received the drugs in reverse order. Serum concentrations of fluvoxamine, caffeine and paraxanthine were measured and standard pharmacokinetic parameters were calculated. Results: There were no significant correlations between caffeine clearance and fluvoxamine oral clearance (r _s= −0.30; P = 0.43) or between the paraxanthine/caffeine ratio in serum 6 h after caffeine intake and fluvoxamine oral clearance (r _s= −0.18; P = 0.58). Conclusion: CYP1A2 does not appear to be of major importance in the metabolism of fluvoxamine. Received: 10 July 1998 / Accepted in revised form: 4 October 1998     

Fluvoxamine and imipramine: results of a long-term controlled trial

Following a multicentre double-blind controlled trial comparing the effects of fluvoxamine and imipramine in depressed inpatients (M.D.E.) 39 patients continued on longer term treatment with maintenance of double-blind conditions (17 on fluvoxamine, 22 on imipramine). The results regarding the reasons for premature interruption of treatment show a slight advantage in favour of fluvoxamine. There were several significant differences in favour of fluvoxamine at the 20th week. The most common side-effects were hot flushes with imipramine and dizziness with fluvoxamine. Overall, despite the small number of patients, the results show a greater clinical tolerance to fluvoxamine than to imipramine.