Biomedical subjects

K Rickels

Publications and source records attributed to K Rickels.

At least 37 records · Page 2Linked to original sources

PubMed1999

Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation.

Long-term (mean, 8 years) users of benzodiazepines (BZs) were administered a small battery of cognitive tests on three occasions (before BZ taper, and 5 and 12 weeks post taper) as part of their BZ discontinuation program. Ninety-six patients had 5-week and 77 patients had 12-week data. For taper successes, BZ-free status was confirmed by weekly BZ plasma level determinations. Age and education, as well as baseline test scores, were used as covariates for all data analyses. Patients who successfully tapered off BZ were able to complete symbol copying (SC) and digit symbol substitution (DSST) tasks faster than patients still taking BZ (p < 0.05). In addition, using an adjective check list, patients with taper success, i.e., BZ-free patients, reported lower levels of mental and physical sedation and higher levels of tranquilization (p < 0.05) than did patients still taking BZ. These results were confirmed in two multiple regression analyses with SC and DSST as the dependent variables. Higher baseline, younger age, and successful taper status (off BZ) were selected as significant independent predictors of SC and DSST scores. In summary, cognitive functions improved for many long-term BZ users after discontinuing their BZ intake.

Adult↗

PubMed1999

Pharmacologic strategies for discontinuing benzodiazepine treatment.

Benzodiazepines have been shown to have broad-spectrum activity, rapid onset of action, and a wide therapeutic window compared with other anxiolytic medications. Yet the use of benzodiazepines has been limited by concern regarding dependence, withdrawal, and abuse. Agents such as antidepressants, serotonergic anxiolytics, anticonvulsants, and beta-blockers have been used with varying degrees of success to help facilitate the tapering of benzodiazepines. Carbamazepine, imipramine, valproate, and trazodone have been beneficial in the management of benzodiazepine discontinuation, but not in decreasing the severity of benzodiazepine withdrawal. A stepwise approach to discontinuing benzodiazepines is offered.

Anti-Anxiety Agents↗

PubMed1999

Characteristics of placebo responses in medical treatment of premenstrual syndrome.

OBJECTIVE: This study characterizes the responses to placebo medication of patients with premenstrual syndrome (PMS) who were randomly assigned in controlled treatment trials. Possible predictors of placebo response were also examined. METHOD: Subjects from two randomized controlled trials were pooled. The 101 subjects met defined criteria for severe PMS, remained eligible after 1 month of single-blind placebo lead-in treatment, and were randomly assigned to 3 months of double-blind placebo treatment. Improvement in the current study was defined as a decrease of at least 50% in premenstrual symptom score from the pretreatment baseline. RESULTS: At endpoint, 20 (20%) of the placebo-treated subjects showed sustained improvement, 18 of these in at least 3 of the 4 months of placebo medication. Another 42% of subjects partially improved, and 39% were clearly unimproved throughout the study period. CONCLUSIONS: Some patients with severe PMS experience significant and sustained improvement with placebo medication, but the majority report only partial or no improvement. Patients who sustain improvement for at least 2 consecutive months are likely to remain improved, indicating the importance of nondrug factors in clinical care.

Adolescent↗

PubMed1998

The effect of personality on withdrawal severity and taper outcome in benzodiazepine dependent patients.

BACKGROUND: Personality psychopathology exerts a significant and independent effect on the course of benzodiazepine (BZ) discontinuation, worsening the subjective severity of withdrawal symptoms and significantly increasing the occurrence of early taper failures. METHOD: One hundred and seventy-one patients participating in a BZ discontinuation programme were administered several personality measures prior to taper. Patients were stabilized for 3 weeks at their baseline BZ dosage and then tapered off 25% per week over 4 weeks, with the option to extend up to 6 weeks if necessary. RESULTS: High levels of passivity and dependency as assessed by the MMPI Dependence subcluster, and at a trend level high Eysenck Neuroticism and high TPQ Harm Avoidance contributed significantly to the prediction of benzodiazepine withdrawal severity. Though there was a high correlation between personality measures, psychopathology and adjusted BZ dose, the effects of personality on withdrawal severity was significant, particularly in the initial phases of BZ taper, when taper severity was still relatively mild. CONCLUSIONS: These findings indicate that clinical decisions on how to manage BZ tapering should be guided by personality assessments, in addition to the usual considerations of BZ dosage, residual psychopathology, duration of treatment, etc. The potential for difficulty with discontinuation related to personality traits should be one of the factors weighted in the risk-benefit assessment made in the planning of benzodiazepine treatment for patients with anxious symptomatology.

Adolescent↗

PubMed1998

Nefazodone in major depression: adjunctive benzodiazepine therapy and tolerability.

One hundred sixty-six patients suffering from major depressive disorders were treated for 8 weeks with nefazodone in an open study in dosage ranges from 200 to 600 mg. This report focuses primarily on the first week of therapy and on the concomitant use of several benzodiazepines, one of which is not metabolized by the cytochrome system (temazepam). Triazolam response was further evaluated as a function of two nefazodone dosage regimens provided during the first week of therapy, one group receiving nefazodone 200 mg/day for 7 days, and another group receiving nefazodone 200 mg/day for 3 days, followed by 4 days with 400 mg/day. Finally, a comparison of three different nefazodone dosages, the third being 400 mg from day 1 on, was also carried out. Outcome measures included Hamilton Rating Scale for Depression total and the total of the three Hamilton Rating Scale for Depression insomnia items, as well as global improvement, a daily completed sleep questionnaire, and adverse event assessment. A combination of nefazodone with a benzodiazepine (BZ) caused more sedation than nefazodone alone; triazolam, the BZ with the shortest half-life and the highest dependence on the cytochrome 450 system for its metabolism, caused the least amount of sedation, and alprazolam and diazepam, the two daytime benzodiazepines, caused the most sedation. Triazolam caused significant and identical reduction of insomnia in both nefazodone groups. Compared with nefazodone 200 mg given as monotherapy, insomnia was significantly improved--not only by triazolam, but also alprazolam and diazepam, but not temazepam. The addition of nefazodone raised triazolam plasma levels to almost 500%, the plasma level of desmethyl-diazepam 87%, and that of alprazolam 34%. Temazepam plasma levels remained unchanged. When prescribing nefazodone with a benzodiazepine, one should expect an improved sleep pattern initially, but at the cost of clinically relevant daytime sedation. The prediction that temazepam, the only BZ not dependent on the cytochrome mechanism for metabolism, should be the least sedating, and triazolam, because of its cytochromic metabolism interference with nefazodone should be the most sedating, could not be confirmed. In fact, triazolam 0.25 mg capsules seem to be the safest treatment of choice when one has to combine a benzodiazepine with nefazodone in initial stages of therapy, at least of the four benzodiazepines tested in this study.

Adult↗

PubMed1998

Panic disorder: long-term pharmacotherapy and discontinuation.

This article compares panic disorder (PD) medications and discusses long-term therapy. In a review of the literature, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and benzodiazepines prove effective in treating PD. MAOIs treat comorbid depression; frequent side effects are dizziness and orthostatic hypotension. SSRIs are better tolerated than MAOIs, producing mild anticholinergic effects, but also producing gastrointestinal side effects and sexual dysfunction. Benzodiazepines are generally well tolerated when titrated gradually; moderate sedation is the most common short-term side effect. Long-term risks are physical dependence and withdrawal reactions. One hundred six PD patients were enrolled in a double-blind, 8-month, placebo-controlled trial of alprazolam and imipramine. In the 8-week short-term phase, daily dosages were titrated up to 10 mg/day of alprazolam and 250 mg/day of imipramine. The greatest number of dropouts occurred during this phase (lack of improvement and/or side effects). Alprazolam patients had a significantly more rapid onset of improvement and lower adverse events and attrition rates. In the 6-month maintenance period, patients continued short-term treatment. Patients receiving either alprazolam or imipramine developed tolerance to some side effects. At maintenance-phase completion, 62% of the alprazolam-group patients and 26% of both the imipramine- and placebo-group patients were panic free (p<0.01). Dosages were tapered to zero over 3 weeks; one third of the alprazolam patients could not discontinue. During the unblinded, 15-month follow-up, patients received open treatment selected by personal physicians on an as-needed basis. At the end of follow-up, all patients were reassessed. Patients who had completed both short-term and maintenance phases were far more likely to be panic-free (85% vs. 55%; p<0.01). PD is chronic and recurrent, and 8 months is an effective treatment period. Maintenance treatment does not lead to tolerance, even with benzodiazepines. Dose tapering must be very gradual. Completion of a long-term maintenance program strongly predicts remission.

Alprazolam↗

PubMed1998

Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management.

The treatment of anxiety has evolved through various phases. Currently, there is a growing recognition that anxiety disorders are frequently chronic and/or recurrent. There is also less optimism than a decade ago that benzodiazepines will be replaced by alternative agents that are not active at the benzodiazepine receptor. Consequently, the understanding and management of benzodiazepine dependence and withdrawal continue to be of some clinical importance. This article briefly reviews the withdrawal syndrome and the pharmacological and patient variables that contribute to it. It then summarizes the various approaches to managing benzodiazepine dependence and withdrawal.

Animals↗

PubMed1998

A randomized, placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major depression.

BACKGROUND: We examined the efficacy and safety of three different dosages of venlafaxine hydrochloride (75, 225, and 375 mg/day) in a multicenter, randomized, double-blind, placebo-controlled, four-group study. METHOD: Outpatients, 18 to 65 years old, who met DSM-III criteria for major depression were included (N = 358 randomized; 194 completed). Of the total patients completing the trial, 59%, 56%, 51%, and 51% were in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. The primary outcome measures were the Hamilton Rating Scale for Depression (HAM-D21) total, HAM-D21 depression item, Montgomery-Asberg Depression Rating Scale total, and Clinical Global Impressions scale. RESULTS: Each dosage of venlafaxine was associated with statistically significant improvement as compared with placebo, based on the intent-to-treat sample. The two higher dosages were associated with a modestly greater antidepressant response than was the 75-mg dosage. Nausea, dizziness, somnolence, and anorexia were the most common adverse events attributable to venlafaxine. Since headache occurred at a similar frequency in both the drug and placebo groups, we did not consider it to be attributable to venlafaxine use. Withdrawal from the study due to adverse events occurred in 5%, 17%, 24%, and 30% of the patients in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. CONCLUSION: Venlafaxine, at dosages of 75-375 mg/day, is an effective and well-tolerated antidepressant. With increasing dosage, greater efficacy and possibly more adverse effects will occur.

Adult↗

PubMed1998

Buspirone and imipramine for the treatment of major depression in the elderly.

BACKGROUND: The current study was designed to assess the safety and efficacy of imipramine and buspirone in the treatment of major depression in elderly depressed attendees of primary care practices. METHOD: 177 patients aged 65 and over (mean age = 72 years; range, 65-89) who met DSM-III-R criteria of unipolar major depression with a minimum Hamilton Rating Scale for Depression score of 18 were randomly assigned to 8 weeks of double-blind, placebo-controlled treatment with flexible doses of either imipramine or buspirone. RESULTS: Moderate to marked global improvement after 8 weeks of treatment (LOCF analysis) occurred in 70% of patients treated with imipramine, 61% of patients treated with buspirone, and 42% of patients treated with placebo (chi2 = 9.1, df = 2, p < .02). Drug treatment was well tolerated, with 77% of imipramine- and 61% of buspirone-treated patients completing 8 weeks of therapy. Imipramine/placebo differences were present from week 2 on, but buspirone/placebo differences occurred only at week 8. The presence of comorbid medical illness or concomitant use of nonpsychiatric prescription medications was not associated with poorer antidepressant response, increased adverse effects, or study attrition. CONCLUSION: Imipramine and to a lesser extent buspirone were found to be effective and well tolerated in the treatment of elderly depressed outpatients.

Age Factors↗

PubMed1998

The spectrum of generalised anxiety in clinical practice: the role of short-term, intermittent treatment.

BACKGROUND: DSM-IV generalised anxiety disorder (GAD) has a high lifetime prevalence, but subthreshold anxiety states are even more common, particularly in family practice. METHOD: Generalized anxiety is conceptualised as a spectrum of disorders, with transient anxiety at one end and GAD at the other. RESULTS: Based on long-term experience with family practice patients, the authors suggest that most anxious patients, wherever on this continuum they are placed, could be treated with short-term, possibly intermittent, rather than chronic anxiolytic therapy. Data are presented which show that 50% of chronic GAD patients are only in need of such short-term intermittent therapy. CONCLUSIONS: Further clinical research is needed to refine short-term, intermittent treatments for anxiety spectrum disorders, to make effective treatments available to those suffering from anxiety but falling short of diagnostic criteria for GAD, and to target more effectively the different treatment strategies.

Acute Disease↗

PubMed1997

Gepirone and diazepam in generalized anxiety disorder: a placebo-controlled trial.

This randomized, double-blind clinical trial involving 198 generalized anxiety disorder (GAD) patients was conducted to more clearly define gepirone's role for the treatment of anxiety in daily dosages of 10 to 45 mg compared with diazepam and placebo. A secondary goal was to test for possible discontinuation symptoms after abrupt discontinuation of therapy. After a 1-week washout period, patients were treated for 8 weeks and then abruptly shifted under single-blind conditions for 2 weeks on placebo. The highest attrition rate occurred with patients on gepirone (58%) and the lowest on diazepam (34%). Medication intake for week 4 was 19.5 +/- 12.5 mg/day diazepam and 19.0 +/- 11.5 mg/day gepirone and was similar at week 8. The major adverse events were light-headedness, nausea, and insomnia for gepirone and drowsiness and fatigue for diazepam. Clinical improvement data showed gepirone's anxiolytic response to be delayed, being significant from placebo beginning at week 6, whereas diazepam caused significantly more relief than placebo from week 1 onward. Taper results showed that only diazepam, but not gepirone, caused a temporary worsening of anxiety symptoms or rebound.

Adult↗

PubMed1997

Strategies for treatment of generalized anxiety in the primary care setting.

Generalized Anxiety Disorder (GAD) is a highly prevalent condition whose course of illness is often chronic in nature and fluctuating in severity. Pharmacotherapy options include the benzodiazepines, the azapirones, of which only buspirone is marketed at the present time, and the antidepressant imipramine. Buspirone is probably the treatment of choice when prolonged therapy is indicated because it does not produce physical dependence, dose not interact with alcohol, and does not cause psychomotor impairment. Dosing instructions for buspirone and guidelines for switching patients from benzodiazepines to buspirone are offered. Non-drug therapies such as interpersonal and cognitive therapies are often also found helpful in treating patients with GAD.

Anxiety Disorders↗

PubMed1997

Gonadotropin-releasing hormone agonist in the treatment of premenstrual symptoms with and without ongoing dysphoria: a controlled study.

Gonadotropin-releasing hormone (GnRH) agonists have been shown to reduce symptoms of premenstrual syndrome (PMS). This randomized, placebo-controlled study examined the efficacy of the GnRH agonist, leuprolide acetate depot, in a clearly defined PMS sample versus women with premenstrual symptoms in combination with dysphoric symptoms throughout the cycle, termed the premenstrual exacerbation (PME) group. Evaluation included the Structured Clinical Interview for DSM-III-R, administered in the follicular phase, and the subject Penn Dally Symptoms Report (DSR) maintained throughout the study. Thirty-three eligible women were randomized to double-blind treatment and administered 3.75 mg of depot leuprolide or a placebo once a month for 3 months. The subjects were seen for efficacy evaluations at the end of each cycle. Outcome measures were the DSRs and the 17-item Hamilton Depression Rating Scale (HAM-D17). The PMS leuprolide subjects improved significantly compared with the PMS placebo and PME leuprolide groups. The PME leuprolide group, who had dysphoric symptoms throughout the cycle, did not improve. Depression symptoms were at clinical levels premenstrually in the PMS and PME groups; following treatment they remitted in the PMS group but not in the PME leuprolide subjects. Efficacy did not occur until after several months of leuprolide treatment, but there was no evidence that PMS symptoms worsened with the onset of treatment. These results replicate the findings in our preliminary open-label study. Leuprolide reduced PMS symptoms to minimal levels where symptoms were limited to the luteal phase. Leuprolide was not effective for women with ongoing dysphoric symptoms, suggesting that premenstrual depression may have mechanisms different from those of other dysphoric mood disorders.

Adult↗

PubMed1997

The clinical presentation of generalized anxiety in primary-care settings: practical concepts of classification and management.

On the basis of our long-term experience in treating family-practice patients and conducting clinical research with them, we propose a practical clinical nosology that takes into account the subsyndromal spectrum of generalized anxiety, as well as patterns of illness, particularly for the family-practice setting. We present an alternative proposal of how to conceptualize generalized anxiety disorders clinically into acute anxiety, subacute anxiety, chronic anxiety, and double anxiety. This is followed by a discussion of the implications for choosing from among the various anxiolytic treatment options available to the family physician and of the importance of the therapeutic context in which treatment is provided. Anxiolytics are not a panacea, but only tools to allow the patient to help himself or herself. Irrespective of which anxiolytic is chosen, and irrespective of the chronicity of the anxiety, short-term (2 to 6 weeks) anxiolytic therapy--if necessary provided more than once on an intermittent basis--should be the treatment approach of first choice. Data are presented to suggest that 50% of all chronically ill patients who have generalized anxiety disorder could benefit from such a treatment approach.

Anti-Anxiety Agents↗

PubMed1997

A double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Abecarnil Work Group.

In a placebo-controlled, multicenter study, 180 male and female outpatients, ages 18-65, with DSM-III-R generalized anxiety disorder, were treated with abecarnil (a partial benzodiazepine agonist), alprazolam, or placebo for 4 weeks. This was followed by a rapid (1-week) taper, during which patients were assessed for any taper-related symptoms. All patients were identified via a structured clinical interview for DSM-III-R and randomly assigned to one of the three treatment groups. More than 70% of each treatment group completed the study. In the acute-treatment phase, both abecarnil and alprazolam showed evidence for efficacy that was significantly better than that of placebo. Both active agents were tolerated well. After the swift taper, a significantly greater number of taper-related symptoms occurred in the alprazolam-treated group than in the abecarnil-treated group, which was not different than in the placebo-treated group. Additionally, less residual improvement followed the taper in the alprazolam-treated and the placebo-treated groups. These data indicate that the partial benzodiazepine agonist abecarnil may be useful as a safe, effective, short-term treatment for anxiety. Theoretical and practical implications of these findings are discussed.

Adolescent↗

PubMed1997

Placebo response in generalized anxiety: its effect on the outcome of clinical trials.

The development of new treatments for generalized anxiety disorder increasingly has been sabotaged by a high placebo-response rate. As a consequence, and in contrast to the surge of approvals for new antidepressants, only one new anxiolytic has been approved by the U.S. Food and Drug Administration in the past 15 years. This article presents a brief review of factors that contribute to the placebo response in treatment studies of generalized anxiety. Since anxiety is a normal emotion that is sensitive to a variety of life stresses, it is particularly difficult to achieve the primary goal of a clinical trial, which is to extract the "signal" of a drug effect from the "noise" of background fluctuations in symptoms. Data from the published literature and from the authors' research unit concerning placebo-response trends are reviewed.

Anti-Anxiety Agents↗

PubMed1996

Reliability and validity of a daily diary for premenstrual syndrome.

Daily ratings of symptoms are essential to confirm a diagnosis of premenstrual syndrome (PMS). The 17-item Daily Symptom Report (DSR) is relatively brief and appropriate for clinical and primary care settings. We report the reliability, factor structure and relationships with other standard mood measures of the DSR as a measure of PMS. The sample includes 170 women who sought medical treatment for severe PMS and a non-clinical comparison group of 54 healthy women in the same age range. Cronbach's coefficient alpha was 0.92 for the premenstrual DSR scores, indicating very high internal consistency for the 17 symptoms. Factor analysis yielded four factors describing mood, behavioral items, pain, and physical symptoms. In the PMS sample, there were moderate correlations between the DSR and the Hamilton Rating Scale for Depression, the Profile of Mood States, and the Premenstrual Assessment Form. The moderate correlations of the DSR with other standard symptom measures add to the evidence that PMS overlaps with other mood disorders at the premenstrual time but is not simply a brief depression or a truncated anxiety disorder.

Adolescent↗

PubMed1996

Zalospirone in major depression: a placebo-controlled multicenter study.

Compounds active at the serotonin (5-HT)1A receptor (mostly azapirones) have shown some evidence of antidepressant effect. We report here the results of an antidepressant trial with zalospirone, a novel cyclic imide with 5-HT1A partial agonist activity. Two hundred eighty-seven outpatients (mean age 44 years, 55% men, 45% nonfertile women) who met criteria for unipolar major depression with a minimum 21-item Hamilton Rating Scale for Depression (HAM-D) score of 20 were randomly assigned to receive 6 weeks of double-blind treatment with either placebo or one of three fixed doses of zalospirone (6, 15, or 45 mg/day), administered three times daily. The high dose (45 mg) of zalospirone produced a significant antidepressant effect compared with placebo from week 2 on with mean improvement (change from baseline) in HAM-D total score of 12.8 versus 8.4 (p < 0.05) at week 6. Clinical improvement with the high dose of zalospirone was consistent across all outcome measures, however, only in the observed cases and not the last-observation-carried-forward analyses. Improvement with the 6-mg or 15-mg doses was greater than that with placebo, but not significantly so, suggesting a dose-response effect. Although the 45-mg dose of zalospirone seemed to have significant antidepressant efficacy, it was not well tolerated. Dizziness and nausea were noted in almost half of the patients, and by week six, 51% of patients in the high-dose group had dropped out. Whether or not tolerance to this high dose might be improved by gradual drug titration, only future research can answer.

Adult↗