Onset of action for duloxetine 60 mg once daily: double-blind, placebo-controlled studies

BACKGROUND: It is widely believed that most antidepressant medications exhibit a delay of 2-4 weeks before clinically relevant improvement can be observed among patients. During this latency period, patients continue to be symptomatic and functionally impaired. Thus, time to onset of effect is an important attribute of a new pharmacotherapy. We assessed the onset of effect for duloxetine, utilizing analytical methods previously recommended in the literature. METHOD: Efficacy data were pooled from two identical, but independent, randomized, double-blind, placebo-controlled, 9-week clinical trials of duloxetine (60 mg QD). Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD(17)), HAMD(17) subscales (Maier, core, and anxiety), and the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales. In each individual study, duloxetine demonstrated statistically significant advantages over placebo on multiple outcomes. The present analysis utilized pooled data to more accurately and fully characterize the onset of effect for duloxetine. RESULTS: Median times to sustained improvements of 10% and 20% in the HAMD(17) total score among duloxetine-treated patients were 14 days and 21 days, respectively, compared with 34 days and 49 days, respectively, for placebo-treated patients (p < 0.001 for both results). The median time to sustained 30% improvement in HAMD(17) total score was 35 days for duloxetine-treated patients, while the median time for placebo-treated patients was not estimable since less than half of the patients met this criterion by the end of the trial. For duloxetine-treated patients, median times to sustained 10%, 20%, and 30% improvements on the Maier subscale of the HAMD(17) were the same as those for the HAMD(17) total score: 14, 21, and 35 days, respectively. However, in other analyses, changes in core emotional symptoms as measured by subscales of the HAMD(17) were somewhat faster than changes in overall symptomatology. The probabilities of achieving a sustained 30% improvement (Maier subscale) at Week 1 for duloxetine- and placebo-treated patients were 16.2% vs. 4.8%, respectively (p < 0.001). The corresponding probabilities of sustained improvement at Weeks 2 and 3 for duloxetine were 32.5% and 45.4%, respectively, compared to 12.8% and 21.4% for placebo ((p < 0.001 for both comparisons). CONCLUSION: The absence of an active comparator limits the conclusions which can be drawn regarding the rapidity of onset of clinically meaningful improvement. However, results from the present investigation may be useful to clinicians in consideration of treatment options for individual patients.     

Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder

Patients with major depressive disorder (MDD) usually suffer from altered cognitive functions of episodic memory, working memory, mental processing speed and motor response. Diverse studies suggest that different antidepressant agents may improve cognitive functions in patients with MDD. The aim of this work is to study the effects of serotonergic reuptake inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments to improve the performance on memory tasks and mental processing speed in MDD. Seventy-three subjects meeting criteria for major depressive disorder were assessed with the Hamilton depression rating scale and a neuropsychological battery. The subjects were medicated with escitalopram (n = 36) or duloxetine (n = 37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same neuropsychological battery used prior to the treatment. Both treatments improved importantly the episodic memory and to a lesser extent, working memory, mental processing speed and motor performance. Our results suggest that cognition is partially independent from improvement in clinical symptoms. Both groups achieved remission rates in the HAM-D-17 after 24 weeks of treatment, but SNRI was superior to SSRI at improving episodic and working memory. Our work indicates that the superiority of SNRI over the SSRI at episodic memory improvement is clinically relevant.     

Potential involvement of NET polymorphism in serotonin/norepinephrine reuptake inhibitor response in panic disorder

Background: This is a pilot study assessing the impact of polymorphisms of serotonin transporter (5-HTT; 5-HTTLPR (S/L)) and norepinephrine transporter (NET; rs2242446 (T/C)) genes on selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) response in Korean panic disorder (PD) patients. Methods: PD patients were treated with SSRI (n?=?18) or SNRI (n?=?6) for 4 weeks. Panic Disorder Severity Scale (PDSS) was rated to evaluate the treatment response. Wilcoxon signed-rank test was used to compare PDSS scores before and after medication (SSRI or SNRI) as well as to compare those according to genotypes. Mann–Whitney U test was used to compare those between the two groups (SSRI or SNRI). Results: Both SSRI and SNRI treatments for 4 weeks significantly reduced PDSS scores. We assessed the impact of rs2242446 on this effect of SSRI and SNRI. The scores were significantly decreased after 4 weeks in the SSRI-treated group regardless of genotypes of rs2242446, whereas they were significantly decreased in the SNRI-treated group with only non-C carrier (TT) of rs2242446. On 5-HTTLPR we could not analyse because 22 patients had SS genotype. Conclusions: These results suggest that NET polymorphism may affect the SNRI response in Korean PD patients.     

Use of the selective serotonin reuptake inhibitor citalopram in treatment of trichotillomania

Previous trials of selective serotonin reuptake inhibitors (SSRIs) in the treatment of trichotillomania have provided conflicting data. Furthermore, the efficacy of citalopram, the most selective of the SSRIs, in trichotillomania has not previously been documented. Citalopram was used on an open-label naturalistic basis in 14 (1 male and 13 females) patients who presented with chronic hair pulling and met DSM-IV criteria for trichotillomania. Ratings were completed every 2 weeks for 12 weeks, during which time dosage was increased to a maximum of 60 mg daily (mean dose 36.2 ± 13.9 mg). One patient was unable to tolerate citalopram. In completers, ratings on each of the scales employed were significantly improved after treatment. Of completers 38.5% were responders (Clinical Global Impressions score of 2 or less) at week 12. Citalopram appears to be safe in trichotillomania, and it may be effective in a subset of patients. Given the relatively low response rate, however, a controlled trial is needed before this agent can be said to be more effective than placebo. The pharmacotherapy of trichotillomania deserves further study.     

Use of bupropion in combination with serotonin reuptake inhibitors.

Incomplete symptom remission and sexual side effects are common problems for which bupropion often is added to treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs) for patients with major depressive disorder (MDD). This article reviews the literature on combining bupropion with SSRIs or SNRIs. We used MEDLINE to select studies that included patients diagnosed with MDD treated with any combination of bupropion and an SSRI or SNRI, either to enhance antidepressant response or to ameliorate antidepressant-associated sexual dysfunction. Bibliographies of located articles were searched for additional studies. Controlled and open-label studies support the effectiveness of bupropion in reversing antidepressant-associated sexual dysfunction, whereas open trials suggest that combination treatment with bupropion and an SSRI or SNRI is effective for the treatment of MDD in patients refractory to the SSRI, SNRI, or bupropion alone. The available data suggest that, although not an approved indication, the combination of bupropion and either an SSRI or an SNRI is generally well tolerated, can boost antidepressant response, and can reduce SSRI or SNRI-associated sexual side effects. Additional randomized controlled studies are needed to answer important questions, such as those regarding optimal dose and duration of treatment.     

Quetiapine addition in obsessive-compulsive disorder: is treatment outcome affected by type and dose of serotonin reuptake inhibitors?

BACKGROUND: The purpose of this study was to assess the effect of type and dose of serotonin reuptake inhibitors (SRIs) on treatment outcome in quetiapine addition trials for obsessive-compulsive disorder. METHODS: Results from all available, double blind, placebo-controlled quetiapine addition trials were pooled. Treatment outcome was assessed in a sample of 102 patients by change from baseline to end point on the Yale-Brown obsessive-compulsive scale (Y-BOCS). RESULTS: Quetiapine addition was superior with a mean Y-BOCS decrease of 6.8 +/- 6.7 compared with placebo with a decrease of 3.9 +/- 6.5 points. Patients with the lowest SRI dose showed the largest decrease on the Y-BOCS (11.6 +/- 7.7) compared with patients with the median dose (6.1 +/- 6.1) and highest dose (5.9 +/- 6.4). CONCLUSIONS: We found a superior response in the quetiapine addition group compared with the placebo group. The best response was achieved with the combination of clomipramine, fluoxetine, and fluvoxamine and with the lowest SRI doses.     

Triple Reuptake Inhibitors: A Premise and Promise

On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant to possible clinical uses for this class of medications.     

Medication algorithm for mood disorders: Present status and future direction in Japan

Medication algorithms have been used extensively in treating psychiatric patients, while geographic variations among these reflect the local history of the practice of psychiatry in each region. Here we review algorithms used for mood disorders in Japan in terms of their utility, problems, and possible future development. The first Japanese algorithm for mood disorders was completed in 1997 by the Japanese Psychopharmacology Algorithm Project (JPAP). Development of the JPAP algorithm was evidence-based, giving major but not exclusive weight to clinical trial outcomes. Unlike others, the JPAP algorithm suggests possible addition of a benzodiazepine to first-line antidepressant treatment for major depression. When the first-choice antidepressant fails, the algorithm recommends monotherapy with another antidepressant over “add-on” therapy. Clinical problems with the JPAP algorithm include lack of guidance concerning how to change from one drug to another. Psychiatry in Japan provides less formal structure for post-graduate education and undertakes less communication with the general public than in many countries. This makes use of an algorithm important for improving quality of practice, provided that clinicians remain aware of the advantages, limitations, and problems of algorithms.     

Induction of mania and cycle acceleration in bipolar disorder: effect of different classes of antidepressant

OBJECTIVE: To assess the effect of different antidepressants on induction of mania and cycle acceleration, commonly accepted unwanted effects of antidepressant treatment for acute bipolar depression. There is, however, the suggestion that certain classes of antidepressants may be less likely than others to cause these unwanted effects. METHOD: We conducted a prospective, open, naturalistic, life charting study to assess the occurrence of onset of mania and cycle acceleration attributable to two antidepressant classes: selective serotonin reuptake inhibitors (SSRIs) and bupropion. RESULTS: No difference was found between the two drug classes for either antidepressant-induced mania or cycle acceleration. Antidepressant-induced mania was much more likely to occur in bipolar I rather than bipolar II patients. The overall occurrence of induction of mania and cycle acceleration was low across antidepressant classes. CONCLUSION: These findings suggest that there is probably no difference in the risk of antidepressant-induced mania or cycle acceleration across commonly used classes of antidepressants for the treatment of bipolar depression.     

Naturalistic study of the early psychiatric use of citalopram in the United States

We obtained information on the efficacy and safety of citalopram in settings that resemble actual clinical practice. A total of 1,783 patients participated in this open, uncontrolled, naturalistic Phase IV evaluation of citalopram at 447 U.S. investigative sites. Participants were selected by guidelines in the citalopram package insert using minimal exclusion criteria. Citalopram dosing began at 20 mg/day and could be titrated to 60 mg/day. Outcomes included the Clinical Global Impressions-Improvement scale (CGI-I) and a Patient Global Evaluation. Separate analyses were performed on patients with a primary diagnosis of major depressive disorder (MDD) (76%) who reported intolerance or nonresponse to previous selective serotonin reuptake inhibitors (SSRIs). Patients included tended to have treatment-resistant or intolerant, chronic or recurrent, comorbid depression with a mean duration of illness of 10 years. At study completion, more than 68% of treatment completers were classified as responders (CGI-I score of 1 or 2). Endpoint analyses showed response rates of 54% in all patients, 56% in patients with MDD, 49% in SSRI nonresponsive patients, and 53% in patients with a history of SSRI intolerance. Nausea (9.8%) and headache (7.3%) were the most often reported adverse events. Patients with a history of SSRI intolerance had a discontinuation rate of 21.8%, whereas those without such a history had a discontinuation rate of 13.3%. Citalopram administered at an average dose of 23.6 mg/day was associated with favorable outcomes and was generally well tolerated.     

A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression

The current study sought to test the efficacy and safety of the novel selective norepinephrine reuptake inhibitor LY2216684 compared to placebo in patients with major depressive disorder (MDD). Escitalopram was used as a control for assay sensitivity. Adult outpatients with MDD, confirmed at screening by the Mini International Neuropsychiatric Interview, a Self-Rated Quick Inventory of Depressive Symptomatology (QIDS-SR) score of at least 12 and a Clinical Global Impression-Severity Score of at least 4, were randomly assigned to LY2216684 (N = 269), placebo (N = 138), or escitalopram (N = 62). Efficacy, safety, and tolerability outcomes were compared during 8 weeks of double-blind treatment. LY2216684 plasma concentrations were measured. LY2216684 did not show statistically significant improvement from baseline compared to placebo in the primary analysis of the Hamilton depression rating scale (HAM-D₁₇) total score. Escitalopram demonstrated significant improvement compared to placebo on the HAM-D₁₇ total score, suggesting adequate assay sensitivity. Both LY2216684 and escitalopram showed statistically significant improvement from baseline on the patient-rated QIDS-SR total score compared to placebo. Headache, nausea, constipation, dry mouth, and insomnia were the most frequently reported adverse events in the LY2216684 group. A 3-6 beats per minute mean increase from baseline in pulse rate was observed in the LY2216684 group. LY2216684 plasma concentrations increased as the dose increased from 3 mg to 12 mg. The results of this initial investigation of LY2216684’s efficacy suggest that it may have antidepressant potential. More definitive data to confirm this is necessary. Its safety profile does not preclude further clinical development.     

Fluoxetine in borderline personality disorder

1. 1. Twelve patients with borderline personality disorder and not suffering a major depression were treated with fluoxetine, a selective serotonin reuptake inhibitor, in an open label trial. All of the patients improved, and 75% were rated as much or very much improved.

2. 2. Treatment was generally very well tolerated, but careful dosage titration was important in some patients, especially to manage agitation.

3. 3. Improvement has been maintained with continued treatment throughout the follow-up period which ranged up to six months.

4. 4. Incidental findings suggest fluoxetine may also be of use in treating substance abuse, attention deficit hyperactivity disorder, late luteal phase dysphoria disorder, dysthymic and cyclothymic disorders, and seasonal pattern depression.

5. 5. These preliminary results support the hypothesis that borderline personality disorder may be related to a central scrotonergic deficit.

Adjunctive antipsychotic in the treatment of body dysmorphic disorder – A retrospective naturalistic case note study

Abstract

Objectives. A retrospective naturalistic case note study to determine the frequency, co-morbidity and treatment-response of body dysmorphic disorder (BDD). Methods. Records from 280 patients attending a highly specialised obsessive-compulsive disorder (OCD)/BDD service were analysed. The clinical outcome was measured either through scoring of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) for OCD/BDD, or textual analysis of case notes for evidence of symptomatic improvement, treatment tolerability, and premature disengagement. Results. A total of 32 patients (11.43%) were diagnosed with BDD. Of these, 28 (87.5%) had at least one co-morbidity. All patients were offered cognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitor (SSRI). Adjunctive low-dose antipsychotic was prescribed for 21 (66%) patients. Overall, 18/32 (56%) responded, and 7/32 (22%) disengaged prematurely. Patients offered antipsychotic, SSRI and CBT (n = 21) were compared with those offered SSRI and CBT only (n = 11). The treatment was well-tolerated. Whereas there was no significant inter-group difference in the clinical response rate, premature disengagement occurred less frequently in the antipsychotic-treated patients (9.5% versus 45%; Fisher's Exact Test P = 0.0318). Conclusions. BDD frequently presents with co-morbidity, treatment-resistance and premature disengagement. Adjunctive antipsychotic was associated with significantly better treatment adherence, but responder rates did not differ significantly, possibly related to the small sample-size. A well-powered randomised controlled study is warranted, to determine clinical outcomes with adjunctive antipsychotic in BDD.     

Besipirdine (HP 749) reduces schedule-induced polydipsia in rats

The aim of the present paper is to report on the adrenergic and serotonergic effects of besipirdine (HP 749) in vivo and to discuss its potential use in the treatment of obsessive compulsive disorder. Besipirdine inhibited biogenic amine uptake in vitro. It prevented tetrabenazine-induced ptosis in mice and potentiated the 5-hydroxytryptophan-induced serotonin syndrome in rats. Furthermore, it decreased schedule-induced polydipsic behavior in rats. Schedule-induced polydipsia may be a model for obsessive compulsive disorder. Previous results from our group have shown that certain selective serotonin reuptake inhibitors decrease schedule-induced polydipsia after 14–21 days of treatment. Besipirdine reduced schedule-induced polydipsic behavior immediately and this reduction lasted throughout the duration of the experiment (29 days).     

Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: A systematic review and meta-analysis of observational studies

This study is a critical analysis of the association between selective serotonin reuptake inhibitors (SSRIs) exposure during pregnancy and autism spectrum disorder (ASD) risk in children. Electronic databases were searched for observational studies published from January 1946 to June 2014 related to the association between SSRI exposure during pregnancy and ASD in children. Studies relevant to the association between SSRI exposure during pregnancy and ASD in children were extracted and compiled for meta-analysis evaluation. Ninety-five citations were identified and seven observational studies were included. Four case–control studies were eligible for the meta-analysis and two cohort studies were narratively reviewed. The pooled crude and adjusted odds ratios of the case–control studies were 2.13 (95% CI 1.66–2.73) and 1.81 (95% CI 1.47–2.24) respectively. Low heterogeneity was observed between studies. The two population-based cohort studies, utilizing the same Denmark data set, have conflicting results. The findings of this meta-analysis and narrative review support an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy; however, the causality remains to be confirmed.     

Drug–drug interactions in general hospital and psychiatric hospital in-patients prescribed psychotropic medications

Objective. To compare the efficacy of verbal, written and, combined verbal and written information about selective serotonin reuptake inhibitors in patients with depression. Method. Patients with a diagnosis of major depression who were prescribed selective serotonin reuptake inhibitors (n=104) were randomly allocated to verbal (n=34, 18F 16M), written (n=38, 19F 19 M) and verbal and written information (n=32, 18F 14M) groups, the content of the verbal and written information being exactly the same. Beck depression inventory was used to evaluate the depressive symptoms. Patients were called back after 10–14 days and their retention of the knowledge was measured. Results. The total retention scores of the verbal group, written group and the combined written and verbal group were 12.85±2.19, 7.39±2.85, and 13.19±2.12, respectively. The total scores of the verbal and the combined verbal and written information groups were significantly higher than those of the written group. The information scores had a significant positive correlation with education level. Conclusion. The retention of verbal information given to patients with low levels of depression concerning the effects and side effects of serotonin reuptake inhibitors is higher than written information. Further studies with more severely depressed patients, comparing the basal information level and the information level after the intervention and the effect of information on compliance are needed.     

Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome

Rett syndrome (RS) is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein2 (MECP2) gene. No effective treatment exists. We previously showed that the Mecp2-deficient mice, a mouse model of RS, have highly variable respiratory rhythm and frequent apneas due to reduced norepinephrine (NE) content, and a drastic decrease of tyrosine hydroxylase (TH)-expressing neurons in the medulla. We showed here that treating these mice with desipramine (DMI), which specifically inhibits NE reuptake, significantly improved their respiratory rhythm during several weeks. In addition, the treatment significantly extended their lifespan. At the cellular level, we showed that the reduced number of TH-expressing neurons before treatment in the mutant animals was not due to apoptosis. Conversely, we found that DMI treatment increased the number of TH-expressing neurons in the mutant brainstem to reach wild-type levels. We showed that this increase was not due to cellular proliferation. We propose that the Mecp2-deficient TH-expressing neurons lose their ability to synthesize TH at some point during their postnatal development. Our results suggest that a pharmacological stimulation of the noradrenergic system could be a promising approach for the treatment of the respiratory dysfunction which causes a significant proportion of death in RS patients.